Systemic and local anti‐C5 therapy reduces the disease severity in experimental autoimmune uveoretinitis

Activation of complement occurs during autoimmune retinal and intraocular inflammatory disease as well as neuroretinal degenerative disorders. The cleavage of C5 into fragments C5a and C5b is a critical event during the complement cascade. C5a is a potent proinflammatory anaphylatoxin capable of inducing cell migration, adhesion and cytokine release, while membrane attack complex C5b‐9 causes cell lysis. Therapeutic approaches to prevent complement‐induced inflammation include the use of blocking monoclonal antibodies (mAb) to prevent C5 cleavage. In these current experiments, the rat anti‐mouse C5 mAb (BB5·1) was utilized to investigate the effects of inhibition of C5 cleavage on disease progression and severity in experimental autoimmune uveoretinitis (EAU), a model of organ‐specific autoimmunity in the eye characterized by structural retinal damage mediated by infiltrating macrophages. Systemic treatment with BB5·1 results in significantly reduced disease scores compared with control groups, while local administration results in an earlier resolution of disease. In vitro, contemporaneous C5a and interferon‐γ signalling enhanced nitric oxide production, accompanied by down‐regulation of the inhibitory myeloid CD200 receptor, contributing to cell activation. These experiments demonstrate that C5 cleavage contributes to the full expression of EAU, and that selective C5 blockade via systemic and local routes of administration can suppress disease. This presents great therapeutic potential to protect against tissue damage during autoimmune responses in the retina or inflammation‐induced degenerative disease.     

Both FcγRIV and FcγRIII are essential receptors mediating type II and type III autoimmune responses via FcRγ‐LAT‐dependent generation of C5a

FcγRIV is a relatively new IgG Fc receptor (FcγR) that is reported to contribute to the pathogenesis of autoimmune diseases, although its specific role in relation to FcγRIII, complement and IgG2 subclasses remains uncertain. Here we define FcγRIV on macrophages as a receptor for soluble IgG2a/b complexes but not for cellular bound IgG2a and show that simultaneous activation of FcγRIV and FcγRIII is critical to mediate certain type II/III autoimmune responses. FcγRIII‐deficient mice display compensatory enhanced FcγRIV expression, are protected from lung inflammation after deposition of IgG complexes, and show reduced sensitivity to IgG2a/b‐mediated hemolytic anemia, indicating that increased FcγRIV alone is not sufficient to trigger these diseases in the absence of FcγRIII. Importantly, however, blockade of FcγRIV is also effective in inhibiting phagocytosis and cytokine production in IgG2b‐induced anemia and acute lung injury, processes that display a further dependence on C5a anaphylatoxin receptor. Using gene deletion and functional inhibition studies, we found that FcγRIII and FcγRIV are each essential to trigger an FcRγ‐linker for activation of T‐cell‐dependent signal that drives C5a production in the Arthus reaction. Together, the results demonstrate a combined requirement for FcγRIII and FcγRIV in autoimmune injury, and identify the linker for activation of T cells adaptor as an integral component of linked FcγR and C5a anaphylatoxin receptor activation to generate inflammation.     

Regulation of CRIg expression and phagocytosis in human macrophages by arachidonate, dexamethasone, and cytokines

Although the importance of the macrophage complement receptor immunoglobulin (CRIg) in the phagocytosis of complement opsonized bacteria and in inflammation has been established, the regulation of CRIg expression remains undefined. Because cellular activation during inflammation leads to the release of arachidonate, a stimulator of leukocyte function, we sought to determine whether arachidonate regulates CRIg expression. Adding arachidonate to maturing human macrophages and to prematured CRIg(+) macrophages caused a significant decrease in the expression of cell-surface CRIg and CRIg mRNA. This effect was independent of the metabolism of arachidonate via the cyclooxygenase and lipoxygenase pathways, because it was not inhibited by the nonsteroidal anti-inflammatory drugs indomethacin and nordihydroguaiaretic acid. Studies with specific pharmacological inhibitors of arachidonate-mediated signaling pathways showed that protein kinase C was involved. Administration of dexamethasone to macrophages caused an increase in CRIg expression. Studies with proinflammatory and immunosuppressive cytokines showed that IL-10 increased, but interferon-γ, IL-4, and transforming growth factor-β1 decreased CRIg expression on macrophages. This down- and up-regulation of CRIg expression was reflected in a decrease and increase, respectively, in the phagocytosis of complement opsonized Candida albicans. These data suggest that a unique inflammatory mediator network regulates CRIg expression and point to a mechanism by which arachidonate and dexamethasone have reciprocal effects on inflammation.     

Inhibition of 4‐1BBL‐regulated TLR response in macrophages ameliorates endotoxin‐induced sepsis in mice

Activation of Toll‐like receptor (TLR) signaling rapidly induces the expression of inflammatory genes, which is persistent for a defined period of time. However, uncontrolled and excessive inflammation may lead to the development of diseases. 4‐1BB ligand (4‐1BBL) plays an essential role in sustaining the expression of inflammatory cytokines by interacting with TLRs during macrophage activation. Here, we show that inhibition of 4‐1BBL signaling reduced the inflammatory responses in macrophages and ameliorated endotoxin‐induced sepsis in mice. A 4‐1BB‐Fc fusion protein significantly reduced TNF production in macrophages by blocking the oligomerization of TLR4 and 4‐1BBL. Administration of 4‐1BB‐Fc suppressed LPS‐induced sepsis by reducing TNF production, and the coadministration of anti‐TNF and 4‐1BB‐Fc provided better protection against LPS‐induced sepsis. Taken together, these observations suggest that inhibition of the TLR/4‐1BBL complex formation may be highly efficient in protecting against continued inflammation, and that 4‐1BB‐Fc could be a potential therapeutic target for the treatment of inflammatory diseases.     

IL‐17A produced by both γδ T and Th17 cells promotes renal fibrosis via RANTES‐mediated leukocyte infiltration after renal obstruction

IL‐17A‐producing T lymphocytes play a crucial role in inflammatory kidney diseases, but their role in renal fibrosis remains to be explored. Here, we demonstrated that up‐regulation of IL‐17A was associated with the development of obstructive kidney injury. The primary source of IL‐17A production in obstructed kidneys was infiltrating γδ T lymphocytes and CD4⁺ T cells. IL‐17A‐deficient mice were protected from myofibroblast activation and extracellular matrix deposition, leading to reduced kidney fibrosis in response to obstructive injury. Mechanistically, IL‐17A deficiency suppressed the expression of the chemokine RANTES in infiltrated CD3⁺ T cells and peritubular inflammation following renal obstruction. Administration of RANTES‐neutralizing antibody significantly reduced the accumulation of T cells and macrophages, and of collagen deposition in obstructed kidneys. Taken together, our results indicate that IL‐17A contributes significantly to the pathogenesis of renal fibrosis by regulating RANTES‐mediated inflammatory cell infiltration. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd     

Functional and structural characterization of four mouse monoclonal antibodies to complement C3 with potential therapeutic and diagnostic applications

C3 is the central component of the complement system. Upon activation, C3 sequentially generates various proteolytic fragments, C3a, C3b, iC3b, C3dg, each of them exposing novel surfaces, which are sites of interaction with other proteins. C3 and its fragments are therapeutic targets and markers of complement activation. We report the structural and functional characterization of four monoclonal antibodies (mAbs) generated by immunizing C3‐deficient mice with a mixture of human C3b, iC3b and C3dg fragments, and discuss their potential applications. This collection includes three mAbs interacting with native C3 and inhibiting AP complement activation; two of them by blocking the cleavage of C3 by the AP C3‐converase and one by impeding formation of the AP C3‐convertase. The interaction sites of these mAbs in the target molecules were determined by resolving the structures of Fab fragments bound to C3b and/or iC3b using electron microscopy. A fourth mAb specifically recognizes the iC3b, C3dg, and C3d fragments. It binds to an evolutionary‐conserved neoepitope generated after C3b cleavage by FI, detecting iC3b/C3dg deposition over opsonized surfaces by flow cytometry and immunohistochemistry in human and other species. Because well‐characterized anti‐complement mAbs are uncommon, the mAbs reported here may offer interesting therapeutic and diagnostic opportunities.     

Intravenous immunoglobulin (IVIg) or IVIg‐treated macrophages reduce DSS‐induced colitis by inducing macrophage IL‐10 production

Intravenous immunoglobulin (IVIg) is used to treat immune‐mediated diseases but its mechanism of action is poorly understood. We have reported that co‐treatment with IVIg and lipopolysaccharide activates macrophages to produce large amounts of anti‐inflammatory IL‐10 in vitro. Thus, we asked whether IVIg‐treated macrophages or IVIg could reduce intestinal inflammation in mice during dextran sulfate sodium (DSS)‐induced colitis by inducing macrophage IL‐10 production in vivo. Adoptive transfer of IVIg‐treated macrophages reduces intestinal inflammation in mice and collagen accumulation post‐DSS. IVIg treatment also reduces DSS‐induced intestinal inflammation and its activity is dependent on the Fc portion of the antibody. Ex vivo, IVIg induces IL‐10 production and reduces IL‐12/23p40 and IL‐1β production in colon explant cultures. Co‐staining tissues for mRNA, we demonstrate that macrophages are the source of IL‐10 in IVIg‐treated mice; and using IL‐10‐GFP reporter mice, we demonstrate that IVIg induces IL‐10 production by intestinal macrophages. Finally, IVIg‐mediated protection is lost in mice deficient in macrophage IL‐10 production (LysMcre^+/?IL‐10^fl/fl mice). Together, our data demonstrate a novel, in vivo mechanism of action for IVIg. IVIg‐treated macrophages or IVIg could be used to treat people with intestinal inflammation and may be particularly useful for people with inflammatory bowel disease, who are refractory to therapy.     

IL‐33 attenuates the development of experimental autoimmune uveitis

Interleukin‐33 (IL‐33) is associated with several important immune‐mediated disorders. However, its role in uveitis, an important eye inflammatory disease, is unknown. Here, we investigated the function of IL‐33 in the development of experimental autoimmune uveitis (EAU). IL‐33 and IL‐33 receptor (ST2) were expressed in murine retinal pigment epithelial (RPE) cells in culture, and IL‐33 increased the expression of Il33 and Mcp1 mRNA in RPE cells. In situ, IL‐33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in EAU mice. ST2‐deficient mice developed exacerbated EAU compared with WT mice, and administration of IL‐33 to WT mice significantly reduced EAU severity. The attenuated EAU in IL‐33‐treated mice was accompanied by decreased frequency of IFN‐γ⁺ and IL‐17⁺ CD4⁺ T cells and reduced IFN‐γ and IL‐17 production but with increased frequency of IL‐5⁺ and IL‐4⁺ CD4 T cells and IL‐5 production in the draining lymph node and spleen. Macrophages from the IL‐33‐treated mice show a significantly higher polarization toward an alternatively activated macrophage phenotype. Our results therefore demonstrate that the endogenous IL‐33/ST2 pathway plays an important role in EAU, and suggest that IL‐33 represents a potential option for treatment of uveitis.     

CRIg signals induce anti‐intracellular bacterial phagosome activity in a chloride intracellular channel 3‐dependent manner

Macrophages provide a first line of defense against bacterial infection by engulfing and killing invading bacteria, but intracellular bacteria such as Listeria monocytogenes (LM) can survive in macrophages by various mechanisms of evasion. Complement receptor of the immunoglobulin (CRIg), a C3b receptor, binds to C3b on opsonized bacteria and facilitates clearance of the bacteria by promoting their uptake. We found that CRIg signaling induced by agonistic anti‐CRIg mAb enhanced the killing of intracellular LM by macrophages, and that this occurred in LM‐containing phagosomes. Chloride intra‐cellular channel 3 CLIC3, an intracellular chloride channel protein, was essential for CRIg‐mediated LM killing by directly interacting with the cytoplasmic domain of CRIg, and the two proteins colocalized on the membranes of LM‐containing vacuoles. CLIC3^?/? mice were as susceptible to LM as CRIg^?/? mice. These findings identify a mechanism embedded in the process by which macrophages take up opsonized bacteria that prevents the bacteria from evading cell‐mediated killing.     

IgE and IL‐33−mediated triggering of human basophils inhibits TLR4−induced monocyte activation

Basophils are circulating granulocytes, best known as effector cells in allergic reactions. Recent studies in mice suggest that they might also participate in the suppression of chronic inflammation. The aim of this study was to assess the ability of purified human basophils to modulate monocyte responses upon IL‐33 and IgE triggering. Activation of human basophils with IL‐33 induced the production of IL‐4 and the release of histamine, and enhanced their IgE‐mediated activation. In addition, basophils triggered with IL‐33 and anti‐IgE significantly suppressed the LPS‐induced production of the proinflammatory cytokine TNF‐α and the upregulation of the costimulatory molecule CD80 by monocytes. These effects were mainly explained by the release of histamine, as they could be inhibited by the histamine receptor 2 antagonist ranitidine, with a smaller contribution of IL‐4. In contrast, basophil‐derived IL‐4 and histamine had opposing effects on the expression of the inhibitory Fc γ receptor IIb and the production of IL‐10 by monocytes. Our data show that basophils can influence monocyte activation and suggest a previously unrecognized role for human basophils in the modulation of monocyte‐mediated immune responses, through the balanced secretion of histamine and IL‐4.     

Interleukin‐33 and alveolar macrophages contribute to the mechanisms underlying the exacerbation of IgE‐mediated airway inflammation and remodelling in mice

Allergen‐specific IgE has long been regarded as a major molecular component of allergic asthma. Additionally, there is increasing evidence of the important roles of interleukin‐33 (IL‐33) in the disease. Here, we show that IL‐33 and alveolar macrophages play essential roles in the exacerbation of IgE‐mediated airway inflammation and remodelling. BALB/c mice passively sensitized with ovalbumin (OVA)‐specific IgE monoclonal antibody (mAb) were challenged with OVA seven times intratracheally. The seventh challenge exacerbated airway inflammation and remodelling compared with the fourth challenge; furthermore, markedly increased expression of IL‐33 in the lungs was observed at the fourth and seventh challenges. When anti‐IL‐33 or anti‐ST2 antibody was administered during the fourth to seventh challenge, airway inflammation and remodelling were significantly inhibited at the seventh challenge. Because increases of IL‐33⁺ and ST2⁺ alveolar macrophages and ST2⁺ CD4⁺ T cells in the lungs were observed at the fourth challenge, the roles of macrophages and CD4⁺ cells were investigated. Depletion of macrophages by 2‐chloroadenosine during the fourth to seventh challenge suppressed airway inflammation and remodelling, and IL‐33 production in the lung at the seventh challenge; additionally, anti‐CD4 mAb inhibited airway inflammation, but not airway remodelling and IL‐33 production. Meanwhile, treatment with 2‐chloroadenosine or anti‐CD4 mAb decreased IL‐33‐induced airway inflammation in normal mice; airway remodelling was repressed only by 2‐chloroadenosine. These results illustrate that macrophage‐derived IL‐33 contributes to the exacerbation of IgE‐mediated airway inflammation by mechanisms associated with macrophages and CD4⁺ cells, and airway remodelling through the activation of macrophages.     

Ex‐vivo tolerogenic F4/80+ antigen‐presenting cells (APC) induce efferent CD8+ regulatory T cell‐dependent suppression of experimental autoimmune uveitis

It is known that inoculation of antigen into the anterior chamber (a.c.) of a mouse eye induces a.c.‐associated immune deviation (ACAID), which is mediated in part by antigen‐specific local and peripheral tolerance to the inciting antigen. ACAID can also be induced in vivo by intravenous (i.v.) inoculation of ex‐vivo‐generated tolerogenic antigen‐presenting cells (TolAPC). The purpose of this study was to test if in‐vitro‐generated retinal antigen‐pulsed TolAPC suppressed established experimental autoimmune uveitis (EAU). Retinal antigen‐pulsed TolAPC were injected i.v. into mice 7 days post‐induction of EAU. We observed that retinal antigen‐pulsed TolAPC suppressed the incidence and severity of the clinical expression of EAU and reduced the expression of associated inflammatory cytokines. Moreover, extract of whole retina efficiently replaced interphotoreceptor retinoid‐binding protein (IRBP) in the preparation of TolAPC used to induce tolerance in EAU mice. Finally, the suppression of EAU could be transferred to a new set of EAU mice with CD8⁺ but not with CD4⁺regulatory T cells (T_reg). Retinal antigen‐pulsed TolAPC suppressed ongoing EAU by inducing CD8⁺ T_reg cells that, in turn, suppressed the effector activity of the IRBP‐specific T cells and altered the clinical symptoms of autoimmune inflammation in the eye. The ability to use retinal extract for the antigen raises the possibility that retinal extract could be used to produce autologous TolAPC and then used as therapy in human uveitis.     

Properdin and factor H production by human dendritic cells modulates their T‐cell stimulatory capacity and is regulated by IFN‐γ

Dendritic cells (DCs) and complement are both key members of the innate and adaptive immune response. Recent experimental mouse models have shown that production of alternative pathway (AP) components by DCs strongly affects their ability to activate and regulate T‐cell responses. In this study we investigated the production and regulation of properdin (fP) and factor H (fH) both integral regulators of the AP, by DCs and tolerogenic DCs (tolDCs). Both fP and fH were produced by DCs, with significantly higher levels of both AP components produced by tolDCs. Upon activation with IFN‐γ both cells increased fH production, while simultaneously decreasing production of fP. IL‐27, a member of the IL‐12 family, increased fH, but production of fP remained unaffected. The functional capacity of fP and fH produced by DCs and tolDCs was confirmed by their ability to bind C3b. Inhibition of fH production by DCs resulted in a greater ability to induce allogenic CD4⁺ T‐cell proliferation. In contrast, inhibition of fP production led to a significantly reduced allostimulatory capacity. In summary, this study shows that production of fP and fH by DCs, differentially regulates their immunogenicity, and that the local cytokine environment can profoundly affect the production of fP and fH.     

A novel “complement–metabolism–inflammasome axis” as a key regulator of immune cell effector function

The inflammasomes are intracellular multiprotein complexes that induce and regulate the generation of the key pro‐inflammatory cytokines IL‐1β and IL‐18 in response to infectious microbes and cellular stress. The activation of inflammasomes involves several upstream signals including classic pattern or danger recognition systems such as the TLRs. Recently, however, the activation of complement receptors, such as the anaphylatoxin C3a and C5a receptors and the complement regulator CD46, in conjunction with the sensing of cell metabolic changes, for instance increased amino acid influx and glycolysis (via mTORC1), have emerged as additional critical activators of the inflammasome. This review summarizes recent advances in our knowledge about complement‐mediated inflammasome activation, with a specific focus on a novel “complement – metabolism – NLRP3 inflammasome axis.”     

Expression of Complement Components and Regulators by Different Subtypes of Bone Marrow-Derived Macrophages

Under inflammatory conditions, macrophages can differentiate into different functional subtypes. We show that bone marrow-derived macrophages constitutively express different levels of various complement-related genes. The relative expression levels are C1qb > Crry > CFH > C3 > C1r > CFB > DAF1 > CD59a > C2 > C1INH > C1s > C4. Upon activation, the expression of C1r, C1s, C3, C2, CFB, and C1INH was up-regulated, and CFH, CD59a, and DAF1, down-regulated in M1 (induced by interferon-γ + lipopolysaccharides (LPS)) and M2b (induced by immune complex + LPS) macrophages. The expression of C4 and CFH was slightly up-regulated in interleukin (IL)-10-induced M2c macrophages. Complement gene expression in IL-4-induced M2a macrophages was weakly down-regulated as compared to resting M0 macrophages. Higher levels of C3, C1INH, and CFB but lower levels of CFH expression in M1 and M2b macrophage suggests that they may be involved in the alternative pathway of complement activation during inflammation.     

Pentraxin 3 recruits complement factor H to protect against oxidative stress‐induced complement and inflammasome overactivation

The discovery that genetic abnormalities in complement factor H (FH) are associated with an increased risk for age‐related macular degeneration (AMD), the most common cause of blindness among the elderly, raised hope of new treatments for this vision‐threatening disease. Nonetheless, over a decade after the identification of this important association, how innate immunity contributes to AMD remains unresolved. Pentraxin 3 (PTX3), an essential component of the innate immunity system that plays a non‐redundant role in controlling inflammation, regulates complement by interacting with complement components. Here, we show that PTX3 is induced by oxidative stress, a known cause of AMD, in the retinal pigmented epithelium (RPE). PTX3 deficiency in vitro and in vivo magnified complement activation induced by oxidative stress, leading to increased C3a, FB, and C3d, but not C5b‐9 complex formation. Increased C3a levels, resulting from PTX3 deficiency, raised the levels of Il1b mRNA and secretion of activated interleukin (IL)‐1β by interacting with C3aR. Importantly, PTX3 deficiency augmented NLRP3 inflammasome activation, resulting in enhanced IL‐1β, but not IL‐18, production by the RPE. Thus, in the presence of PTX3 deficiency, the complement and inflammasome pathways worked in concert to produce IL‐1β in sufficient abundance to, importantly, result in macrophages accumulating in the choroid. These results demonstrate that PTX3 acts as an essential brake for complement and inflammasome activation by regulating the abundance of FH in the RPE, and provide critical insights into the complex interplay between oxidative stress and innate immunity in the early stages of AMD development. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Activated mast cells synthesize and release soluble ST2‐a decoy receptor for IL‐33

IL‐33 released from damaged cells plays a central role in allergic inflammation by acting through its membrane‐bound receptor, ST2 receptor (ST2L). IL‐33 activity can be neutralized by the soluble spliced variant of ST2 (sST2) that has been associated with allergic inflammation but its source is not well defined. We investigated whether mast cells (MCs) are a significant source of sST2 following activation through FcεRI or ST2. We find that antigen and IL‐33 induce substantial production and release of sST2 from human and mouse MCs in culture and do so synergistically when added together or in combination with stem cell factor. Moreover, increases in circulating sST2 during anaphylaxis in mice were dependent on the presence of MCs. Human MCs activated via FcεRI failed to generate IL‐33 and IL‐33 produced by mouse bone marrow‐derived MCs was retained within the cells. Therefore, FcεRI‐mediated sST2 production is independent of MC‐derived IL‐33 acting in an autocrine manner. These results are consistent with the conclusion that both mouse and human MCs when activated are a significant inducible source of sST2 but not IL‐33 and thus have the ability to modulate the biologic impact of IL‐33 produced locally by other cell types during allergic inflammation.     

A role for interleukin‐17A in modulating intracellular survival of Mycobacterium bovis bacillus Calmette–Guérin in murine macrophages

Interleukin 17A IL‐17A is a crucial immunomodulator in various chronic immunological diseases including rheumatoid arthritis and inflammatory bowel disease. The cytokine has also been demonstrated to control the pathogenesis of the Mycobacterium tuberculosis by dysregulating production of cytokines and chemokines and promoting granuloma formation. Whether IL‐17A regulates innate defence mechanisms of macrophages in response to mycobacterial infection remains to be elucidated. In the current report, we investigated the effects of IL‐17A on modulating the intracellular survival of Mycobacterium bovis bacillus Calmette–Guérin (BCG) in RAW264.7 murine macrophages. We observed that IL‐17A pre‐treatment for 24 hr was able to synergistically enhance BCG‐induced nitric oxide (NO) production and inducible nitric oxide synthase expression in dose‐ and time‐dependent manners. We further delineated the mechanisms involved in this synergistic reaction. IL‐17A was found to specifically enhanced BCG‐induced phosphorylation of Jun N‐terminal kinase (JNK), but not of extracellular signal‐regulated kinase 1/2 and p38 mitogen‐activated protein kinase. By using a specific JNK inhibitor (SP600125), we found that the production of NO in BCG‐infected macrophages was significantly suppressed. Taken together, we confirmed the involvement of the JNK pathway in IL‐17A‐enhanced NO production in BCG‐infected macrophages. We further demonstrated that IL‐17A significantly enhanced the clearance of intracellular BCG by macrophages through an NO‐dependent killing mechanism. In conclusion, our study revealed an anti‐mycobacterial role of IL‐17A through priming the macrophages to produce NO in response to mycobacterial infection.     

Targeted IgA Fc receptor I (FcαRI) therapy in the early intervention and treatment of pristane‐induced lupus nephritis in mice

The Fc receptor I for IgA (FcαRI) down‐regulates humoral immune responses and modulates the risk of autoimmunity. This study aimed to investigate whether FcαRI targeting can affect progression of pristine‐induced lupus nephritis. In the first experiment (early intervention), four groups of animals were evaluated: untreated FcαRI/FcRγ transgenic (Tg) mice and Tg mice administered control antibody (Ctr Fab), saline and anti‐FcαRI Fab [macrophage inflammatory protein (MIP)‐8a], respectively, three times a week for 29 weeks, after being injected once intraperitoneally with 0·5 ml pristane. In the second experiment, antibody injection started after the onset of nephritis and was carried out for 2 months, with similar groups as described above. MIP‐8a improved proteinuria, decreased the amounts of glomerular injury markers, serum interleukin (IL)‐6, IL‐1 and monocyte chemoattractant protein (MCP)‐1, and F4/80 macrophages in the interstitium and glomeruli, in both experiments. When MIP‐8a was used as early intervention, a decrease in mouse serum anti‐nuclear antibody (ANA) titres and reduced deposition of immunoglobulins in glomeruli were observed. This effect was associated with reduced serum titres of immunoglobulin (Ig)G2a but not IgG1, IgG2b and IgG3. Furthermore, pathological analysis showed lower glomerular activity index and less fibronectin in MIP‐8a treated mice. This study suggests that FcαRI targeting could halt disease progression and lupus activation by selective inhibition of cytokine production, leucocyte recruitment and renal inflammation. Our findings provide a basis for the use of FcαRI as a molecular target for the treatment of lupus.