Pulmonary surfactant proteins and lipids as modulators of inflammation and innate immunity

Objectives: The pulmonary surfactant system of the human lung consists of unique lipids and proteins that contribute to the biophysical and innate immune properties of the organ. Surfactant protein A (SP‐A) is an oligomeric protein consisting of 18 protomers with collagen and lectin–like domains that recognizes glycoconjugates, lipids and protein determinants on both host cells and invading microorganisms. The authors examined the interaction of SP‐A with Mycoplasma pneumoniae and the influence of the protein upon the innate immune response to the bacteria. Methodology: The authors quantified SP‐A interaction with bacteria using ELISA, and identified the major surface ligand by thin layer chromatography, HPLC and mass spectrometry. The inflammatory response of human and rat macrophages was measured by quantifying tumour necrosis factor‐α secretion using ELISA, and nitric oxide production. Results: SP‐A bound the bacteria with high affinity and enhanced the inflammatory response of human and rat macrophages to the organism and its membranes. Analysis of the interaction of SP‐A with the bacteria revealed that the major ligand was a phospholipid. The lipid ligand was purified by a combination of thin layer and HPLC, and identified by mass spectrometry. The mass spectrometry demonstrated that the SP‐A reactive lipid consisted of several disaturated molecular species of phosphatidylglycerol (PtdGro). Additional experiments were performed to determine if disaturated PtdGro was capable of interfering with the action of SP‐A as an inhibitor of bacterial lipopolysaccharide‐induced inflammatory mediator production by macrophages. The disaturated PtdGro failed to alter the anti‐inflammatory action of SP‐A but unexpectedly these same studies revealed that unsaturated PtdGro can modify the host response to lipopolysaccharide. Conclusions: These findings reveal that both the lipids and proteins of pulmonary surfactant play a role in regulating the host response to invading microorganisms.     

Pulmonary surfactant in innate immunity and the pathogenesis of tuberculosis.

Components of the innate immune system serve to protect the host from invading pathogens prior to the generation of a directed immune response, and influence the manner in which the directed immune response develops. The pulmonary surfactant system consists of a complex array of proteins and lipids that reduce surface tension of the alveoli, and appears to play an essential role in innate immunity. Investigators have recently gained insight into the interactions between components of the surfactant system and the respiratory pathogen Mycobacterium tuberculosis. It is likely that pulmonary surfactant and other innate immune determinants play significant roles in the pathogenesis of tuberculosis.     

Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity

Acetaminophen (APAP) hepatotoxicity because of overdose is the most frequent cause of acute liver failure in the western world. Metabolic activation of APAP and protein adduct formation, mitochondrial dysfunction, oxidant stress, peroxynitrite formation and nuclear DNA fragmentation are critical intracellular events in hepatocytes. However, the early cell necrosis causes the release of a number of mediators such as high‐mobility group box 1 protein, DNA fragments, heat shock proteins (HSPs) and others (collectively named damage‐associated molecular patterns), which can be recognized by toll‐like receptors on macrophages, and leads to their activation with cytokine and chemokine formation. Although pro‐inflammatory mediators recruit inflammatory cells (neutrophils, monocytes) into the liver, neither the infiltrating cells nor the activated resident macrophages cause any direct cytotoxicity. In contrast, pro‐ and anti‐inflammatory cytokines and chemokines can directly promote intracellular injury mechanisms by inducing nitric oxide synthase or inhibit cell death mechanisms by the expression of acute‐phase proteins (HSPs, heme oxygenase‐1) and promote hepatocyte proliferation. In addition, the newly recruited macrophages (M2) and potentially neutrophils are involved in the removal of necrotic cell debris in preparation for tissue repair and resolution of the inflammatory response. Thus, as discussed in detail in this review, the preponderance of experimental evidence suggests that the extensive sterile inflammatory response during APAP hepatotoxicity is predominantly beneficial by limiting the formation and the impact of pro‐inflammatory mediators and by promoting tissue repair.     

Gastrointestinal inflammation: lessons from metabolic modulators

The link between inflammation and metabolism was apparent already early last century, but has recently been revitalized following molecular studies of atherosclerosis, obesity and insulin resistance. A growing list of nuclear receptors, pivotal players in lipid, xenobiotic and energy metabolism has been identified as having immunomodulatory functions. These receptors might hold the key to some of the questions pertinent to chronic inflammation, and can lend themselves to be manipulated as therapeutic agents. This review will attempt to appraise the importance of such mediators in the pathophysiology of chronic inflammation in the colon.     

Studies on patients establish Crohn's disease as a manifestation of impaired innate immunity

The fruitless search for the cause of Crohn's disease has been conducted for more than a century. Various theories, including autoimmunity, mycobacterial infection and aberrant response to food and other ingested materials, have been abandoned for lack of robust proof. This review will provide the evidence, obtained from patients with this condition, that the common predisposition to Crohn's is a failure of the acute inflammatory response to tissue damage. This acute inflammation normally attracts large numbers of neutrophil leucocytes which engulf and clear bacteria and autologous debris from the inflamed site. The underlying predisposition in Crohn's disease is unmasked by damage to the bowel mucosa, predominantly through infection, which allows faecal bowel contents access to the vulnerable tissues within. Consequent upon failure of the clearance of these infectious and antigenic intestinal contents, it becomes contained, leading to a chronic granulomatous inflammation, producing cytokine release, local tissue damage and systemic symptoms. Multiple molecular pathologies extending across the whole spectrum of the acute inflammatory and innate immune response lead to the common predisposition in which defective monocyte and macrophage function plays a central role. Family linkage and exome sequencing together with GWAS have identified some of the molecules involved, including receptors, molecules involved in vesicle trafficking, and effector cells. Current therapy is immunosuppressant, which controls the symptoms but accentuates the underlying problem, which can only logically be tackled by correcting the primary lesion/s by gene therapy or genome editing, or through the development of drugs that stimulate innate immunity.     

Heat-shock proteins as endogenous ligands building a bridge between innate and adaptive immunity

There has been growing evidence that heat-shock protein (HSP) functions as an endogenous immunomodulator for innate and adaptive immune responses. Since HSPs inherently act as chaperones within cells, passive release (e.g., by cell necrosis) and active release (including release by secretion in the form of an exosome) have been suggested as mechanisms of HSP release into the extracellular milieu. Such extracellular HSPs have been shown to be activators of innate immune responses through Toll-like receptors. However, it has also been suggested that HSPs augment the ability of associated innate ligands such as lipopolysaccharides to stimulate cytokine production and dendritic cell maturation. More interestingly, a recent study has demonstrated that innate immune responses elicited by danger signals were regulated spatiotemporally and that can be manipulated by HSPs, thereby controlling immune responses. We will discuss how spatiotemporal regulation of HSP-chaperoned molecules within antigen-presenting cells affects adaptive immunity via antigen cross-presentation and innate immune responses. Precise analysis of HSP biology should lead to the establishment of effective HSP-based immunotherapy.     

Identification of innate immunity genes and pathways using a comparative genomics approach

To reveal regulators of innate immunity, we used RNAi assays to monitor the immune response when genes are inhibited in Caenorhabditis elegans and mouse macrophages. Genes that altered innate immune responsiveness in C. elegans were validated in murine macrophages, resulting in the discovery of 11 genes that regulate the innate immune response in both systems and the subsequent identification of a protein interaction network with a conserved role in innate immunity regulation. We confirmed the role of four of these 11 genes in antimicrobial gene regulation using available mutants in C. elegans. Several of these genes (acy-1, tub-2, and tbc-1) also regulate susceptibility to the pathogen Pseudomonas aeruginosa. These genes may prove critical to understanding host defense and represent potential therapeutic targets for infectious and immunological diseases.     

Antagonism of innate immunity by paramyxovirus accessory proteins

Paramyxovirinae, a subfamily of Paramyxoviridae, are negative strand RNA viruses comprised of many important human and animal pathogens, which share a high degree of genetic and structural homology. The accessory proteins expressed from the P/V/C gene are major factors in the pathogenicity of the viruses, because of their ability to abrogate various facets of type I interferon (IFN) induction and signaling. Most of the paramyxoviruses exhibit a commonality in their ability to antagonize innate immunity by blocking IFN induction and the Jak/STAT pathway. However, the manner in which the accessory proteins inhibit the pathway differs among viruses. Similarly, there are variations in the capability of the viruses to counteract intracellular detectors (RNA helicases, mda-5 and RIG-I). Furthermore, a functional specificity in the antagonism of the IFN response has been reported, suggesting that specificity in the circumvention of innate immunity restricts viral host range. Available evidence indicates that paramyxoviruses employ specific strategies to antagonize the IFN response of their specific hosts, which is one of the major factors that determine viral pathogenicity and host range.     

先天性免疫在钙化性主动脉瓣疾病中的作用

钙化性主动脉瓣疾病(CAVD)是影响心脏瓣膜的最常见疾病,其特征是主动脉瓣瓣小叶的增厚、纤维化和矿化,目前尚无有效的药物治疗。主动脉瓣钙化是一个复杂的、多因素影响的过程,包括瓣膜炎症、纤维化、钙化以及瓣膜增厚和心流出道阻塞。CAVD的确切病理生理机制尚不完全清楚,但许多研究表明先天免疫细胞在主动脉瓣钙化的发展中起关键作用。该综述主要阐述目前关于先天性免疫细胞在CAVD发展中的作用。     

长链非编码RNAs在抗病毒固有免疫中研究进展

长链非编码RNAs（long non-coding RNAs, lncRNAs）作为一类重要的调控分子,在表观遗传学、转录及转录后等多水平参与免疫反应调控。在抗病毒固有免疫反应中,lncRNAs主要通过与蛋白质、DNA、微小RNA、信使RNA等互作来发挥调节作用;与此同时,病毒亦可通过自身lncRNAs作用于宿主参与免疫逃逸。本文概括了lncRNAs在调控抗病毒固有免疫中的重要作用和相关机制,以及lncRNAs在宿主-病毒互作中免疫逃逸等最新研究进展,以期对病毒感染性疾病提供新的研究思路和诊疗方法。     

炎症Caspase调控固有免疫在心血管疾病中的作用

越来越多的证据表明,慢性炎症与高血压、动脉粥样硬化等心血管疾病密切相关。半胱天冬氨酸蛋白水解酶(Caspase)亚型Caspase-1、4、5和11被称为炎症Caspase,通过促进炎症因子的成熟与释放,诱导放大炎症反应,激活固有免疫应答。炎症Caspase作用机制包括两方面,一方面激活模式识别受体NLRP3炎症小体,促进炎症因子白细胞介素1β(IL-1β)和IL-18的剪切成熟,另一方面剪切Gasdermin D形成具有膜上打孔作用的N端,导致细胞焦亡,促进炎症因子释放。文章就炎症Caspase在心血管疾病中的作用进行综述。     

Distribution of intracellular and secreted surfactant during postnatal rat lung development

Pulmonary surfactant prevents alveolar collapse via reduction of surface tension. In contrast to human neonates, rats are born with saccular lungs. Therefore, rat lungs serve as a model for investigation of the surfactant system during postnatal alveolar formation. We hypothesized that this process is associated with characteristic structural and biochemical surfactant alterations. We aimed to discriminate changes related to alveolarization from those being either invariable or follow continuous patterns of postnatal changes. Secreted active (mainly tubular myelin (tm)) and inactive (unilamellar vesicles (ulv)) surfactant subtypes as well as intracellular surfactant (lamellar bodies (lb)) in type II pneumocytes (PNII) were quantified before (day (d) 1), during (d 7), at the end of alveolarization (d 14), and after completion of lung maturation (d 42) using electron microscopic methods supplemented by biochemical analyses (phospholipid quantification, immunoblotting for SP-A). Immunoelectron microscopy determined the localization of surfactant protein A (SP-A). (1) At d 1 secreted surfactant was increased relative to d 7-42 and then decreased significantly. (2) Air spaces of neonatal lungs comprised lower fractions of tm and increased ulv, which correlated with low SP-A concentrations in lung lavage fluid (LLF) and increased respiratory rates, respectively. (3) Alveolarization (d 7-14) was associated with decreasing PNII size although volume and sizes of Lb continuously increased. (4) The volume fractions of Lb correlated well with the pool sizes of phospholipids in lavaged lungs. Our study emphasizes differential patterns of developmental changes of the surfactant system relative to postnatal alveolarization.     

Beyond neurotransmission: acetylcholine in immunity and inflammation

Acetylcholine (ACh) is best known as a neurotransmitter and was the first such molecule identified. ACh signalling in the neuronal cholinergic system has long been known to regulate numerous biological processes (reviewed by Beckmann and Lips). In actuality, ACh is a ubiquitous signalling molecule that is produced by numerous non‐neuronal cell types and even by some single‐celled organisms. Within multicellular organisms, a non‐neuronal cholinergic system that includes the immune system functions in parallel with the neuronal cholinergic system. Several immune cell types both respond to ACh signals and can directly produce ACh. Recent work from our laboratory has demonstrated that the capacity to produce ACh is an intrinsic property of T cells responding to viral infection, and that this ability to produce ACh is dependent upon IL‐21 signalling to the T cells. Furthermore, during infection this immune‐derived ACh is necessary for the T cells to migrate into infected tissues. In this review, we will discuss the various sources of ACh that are relevant during immune responses and describe how ACh acts on immune cells to influence their functions. We will also address the clinical implications of this fascinating aspect of immunity, focusing on ACh’s role in the migration of T cells during infection and cancer.     

Ovulation as danger signaling event of innate immunity

The ovulatory process is characterized by tissue wounding and, after oocyte expulsion, by healing being connected to the formation of a corpus luteum (CL). The ovulatory event thus compares with a sterile inflammation. The concept is forwarded that the ovulatory process depends on innate immunity (INIM) function. The ultimate trigger for INIM signaling are danger signals/alarmins from granulosa cells damaged by oxidative stress and reactive oxygen species (ROS), respectively. Alarmins like oxidized low density lipoprotein (oxLDL) are recognized by cytokeratin-positive (CK(+)) granulosa cells with the expression of toll-like receptor 4 (TLR4). The subsequent inside-out signaling from the antrum towards the thecal cell layer comprises inflammation and tissue disintegration, which might be dominated by the myeloid differentiation factor 88 (Myd88) gateway. Additive or co-regulatory function are expected from the complement cascade for vessel permeability and leukocyte immigration and the wingless (WnT)-signaling for cell adhesion of CK(+) granulosa cells. The outside-in signaling relates to the repair phase, which is primarily controlled by the TIR-domain-containing adaptor protein producing IFN type I (TRIF) gateway of TLR signaling. The KIT/CD117 tyrosine kinase receptor and the tachykinin-tachykinin receptor system could be involved. The appealing concept of INIM function in the ovary is novel and inaugurates a novel research field.     

Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice

During injury to the nervous system, innate immune cells mediate phagocytosis of debris, cytokine production, and axon regeneration. In the neuro-degenerative disease amyotrophic lateral sclerosis (ALS), innate immune cells in the CNS are activated. However, the role of innate immunity in the peripheral nervous system (PNS) has not been well defined. In this study, we characterized robust activation of CD169/CD68/Iba1+ macrophages throughout the PNS in mutant SOD1^G93A and SOD1^G37R transgenic mouse models of ALS. Macrophage activation occurred pre-symptomatically, and expanded from focal arrays within nerve bundles to a tissue-wide distribution following symptom onset. We found a striking dichotomy for immune cells within the spinal cord and PNS. Flow cytometry and GFP bone marrow chimeras showed that spinal cord microglia were mainly tissue resident derived, dendritic-like cells, whereas in peripheral nerves, the majority of activated macrophages infiltrated from the circulation. Humoral antibodies and complement localized to PNS tissue in tandem with macrophage recruitment, and deficiency in complement C4 led to decreased macrophage activation. Therefore, cross-talk between nervous and immune systems occurs throughout the PNS during ALS disease progression. These data reveal a progressive innate and humoral immune response in peripheral nerves that is separate and distinct from spinal cord immune activation in ALS transgenic mice.