HMGB1 released from nociceptors mediates inflammation

Inflammation, the body’s primary defensive response system to injury and infection, is triggered by molecular signatures of microbes and tissue injury. These molecules also stimulate specialized sensory neurons, termed nociceptors. Activation of nociceptors mediates inflammation through antidromic release of neuropeptides into infected or injured tissue, producing neurogenic inflammation. Because HMGB1 is an important inflammatory mediator that is synthesized by neurons, we reasoned nociceptor release of HMGB1 might be a component of the neuroinflammatory response. In support of this possibility, we show here that transgenic nociceptors expressing channelrhodopsin-2 (ChR2) directly release HMGB1 in response to light stimulation. Additionally, HMGB1 expression in neurons was silenced by crossing synapsin-Cre (Syn-Cre) mice with floxed HMGB1 mice (HMGB1^f/f). When these mice undergo sciatic nerve injury to activate neurogenic inflammation, they are protected from the development of cutaneous inflammation and allodynia as compared to wild-type controls. Syn-Cre/HMGB1^fl/fl mice subjected to experimental collagen antibody–induced arthritis, a disease model in which nociceptor-dependent inflammation plays a significant pathological role, are protected from the development of allodynia and joint inflammation. Thus, nociceptor HMGB1 is required to mediate pain and inflammation during sciatic nerve injury and collagen antibody–induced arthritis.

The dual threat of infection and injury exerted a significant influence on the evolution of the mammalian immune and nervous systems. The nervous system detects changes in the environment, generates reflexive responses to those changes, and integrates these responses across space and time to establish adaptive memories of events (1, 2). Sensory neurons, termed nociceptors, innervate tissues subjected to infection and injury and are activated by the molecular products of microbes and tissue injury (3–6). Nociceptor signaling stimulates reflexive neural circuits to coordinate defensive behavior, including inflammation (3–9). Reflex neural signaling arising in the brain and spinal cord is capable of integrating divergent stimulating and inhibitory inputs, because neural signaling circuits act in opposition (10, 11). This balance of opposing signals enables fine tuning of physiological responses by smoothing gradients of corrective action in response to a changing environment (12). Evolutionary pressure from infection and injury also molded the mammalian immune system to detect changes in the environment, mobilize coordinated defensive reactions, and establish memory (13). The acute onset of infection and injury produces inflammation, defined by pain, edema, heat, redness, and loss of function mediated by immune cells producing cytokines and other inflammatory mediators (6, 14). Because uninhibited inflammation also causes dangerous shock and lethal tissue injury, homeostatic mechanisms at the intersection of the nervous system and immune system have a fundamental role in health by inhibiting inflammation (15–17).The nervous system inhibits inflammation by transmitting antiinflammatory signals in the vagus nerve, which arises in the brainstem and sends efferent projections to the organs (15–18). In the inflammatory reflex, signals descend from the brain to the abdominal celiac mesenteric ganglia, the origin of the splenic nerve (19, 20). In the spleen, splenic nerve signals stimulate a subset of T lymphocytes to secrete acetylcholine, which interacts with alpha 7 nicotinic acetylcholine receptors to inhibit macrophage production of TNF and other inflammatory mediators (21–23). Detailed mechanistic insight into the neuroscience, functional immunology, and molecular mechanisms of the inflammatory reflex enabled therapeutic trials using vagus nerve stimulation to inhibit inflammation in humans. This strategy to stimulate the inflammatory reflex inhibits cytokine release and suppresses inflammation in patients with inflammatory bowel disease and rheumatoid arthritis (24–26). Since evolution selects for reflexively controlled homeostatic systems acting antagonistically, here we reasoned it likely also selected for neural reflex circuits which stimulate inflammation and enhance immunity.High mobility group box 1 protein (HMGB1), a ubiquitous nuclear protein conserved across evolution from archaea to mammals, is a necessary and sufficient mediator of sterile injury- and infection-elicited inflammation and immunity (27, 28). It is passively released by cells undergoing necrosis and secreted by innate immune cells activated by inflammation (27, 29). HMGB1 stimulates inflammation by activating the receptor for advanced glycation end products (RAGE) and Toll-like receptor 2, 4, and 9 (TLR 2, 4, and 9) expressed by many different cell types (30–32). Signal transduction via these receptors culminates in increased expression of cytokines, and in recruiting and stimulating monocytes, lymphocytes, and neutrophils. HMGB1 also stimulates dendritic cell maturation and enhances antibody responses to antigen, an important early stage in memory formation (33, 34). Administration of HMGB1 antagonists significantly attenuates the severity of inflammation in preclinical models of sepsis, inflammatory bowel disease, arthritis, and neuroinflammation (31, 32, 35, 36).HMGB1 is expressed in the nervous system in cortical neurons and in nociceptors (37–40). In preclinical models of nerve injury, HMGB1 levels are increased in the cell bodies of nociceptors residing in the dorsal root ganglia (DRG) (39, 40). In brain neurons, HMGB1 translocates into the cytoplasm and is released during ischemia (38, 41). Exposure of cortical neurons to ethanol activates HMGB1 release via a mechanism dependent upon NOX2/NLRP1 inflammasome (42). Neuronal HMGB1 expression is also significantly enhanced during nerve injury (39, 43, 44). Because HMGB1 stimulates inflammation, and is expressed by nociceptors, and since nociceptors provide a ubiquitous network of nervous system connectivity to peripheral tissues, we reasoned HMGB1 released by nociceptors is a mechanism of neurogenic inflammation. Here, utilizing neuronal-specific ablation of HMGB1 (Syn-Cre/HMGB1^fl/fl mice), we discovered a specific role for neuron-derived HMGB1 in inflammation. Genetic silencing of HMGB1 in neurons attenuates inflammation after sciatic nerve injury and in collagen antibody–induced polyarthritis revealing a previously unexpected, but essential, mechanistic role for neuronal HMGB1 in inflammation.     

Cutaneous Malignancies in Xeroderma Pigmentosum: Earlier Management Improves Survival

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease, characterized by hypersensitivity of the skin to ultraviolet (UV) radiation leading to high incidence of skin cancer and progressive neurological complications. It results in premature development of neoplasias due to an exacerbated hypersensitivity to UV radiation causing premalignant and malignant lesions leading to death in early adulthood. Two cases of clinical features of xeroderma pigmentosa with skin lesions were managed in our department. One had multiple clusters of basal and squamous cell carcinomas and the other had malignant melanomas and right neck nodes. Both were treated with multiple wide excisions and the neck node were surgically managed with radical neck dissections. Skin malignancies were common in the sun exposed areas and patients were advised regular 3 months follow up. The disease is ultimately fatal, life can be prolonged by simple preventive measures to minimize sun exposure. Comprehensive multimodality management includes patient education and counselling for the psychosomatic disorder and genetic counseling remains the most important preventive measure.     

The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals.

Indinavir (IDV) is a potent and selective human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) widely used in antiretroviral therapy for suppression of HIV, but its effects on the immune system are relatively unknown. Recently, it has been reported that PIs inhibit lymphocyte apoptosis. In the present study we have investigated the effects of ex vivo addition of IDV on lymphocyte activation and apoptosis in cells from HIV-infected children (n = 18) and from healthy uninfected individuals (controls, n = 5) as well as in Jurkat and PM1 T-cell lines. Pretreatment of control peripheral blood mononuclear cell (PBMC) cultures with IDV resulted in a dose-dependent inhibition of lymphoproliferative responses to different activation stimuli. Additionally, this treatment led to cell-cycle arrest in G0/G1 phase in anti-CD3 monoclonal antibody-stimulated PBMC cultures in controls and in 15 of 18 HIV-infected children. Spontaneous- or activation-induced apoptosis of PBMCs from HIV-infected or uninfected individuals or of Fas-induced apoptosis in Jurkat and PM1 T cell lines were not inhibited by IDV. Moreover, IDV did not inhibit activation of caspases-1, -3, -4, -5, -9, and -8 in lysates of Jurkat T cells undergoing Fas-induced apoptosis. The findings indicate that IDV interferes with cell-cycle progression in primary cells but does not directly affect apoptosis. It is concluded that IDV may prolong cell survival indirectly by inhibiting their entry into cell cycle. In individuals on PI therapy, PI-mediated effects could potentially modulate immunologic responses independently of antiviral activity against HIV.     

The mini-rhino-conjunctivitis quality of life (qol) questionnaire (mrqlq) — self administered

Objective

Our aim was to administer the MRQLQ Questionnaire in Indian adults with allergic rhino-conjunctivitis (ARc).

Criteria for inclusion in the study

Adults with chronic ARc, with sufficiently troublesome current symptoms, attending The Allergy Clinic of The Hinduja Hospital, Mumbai, during March–August 2006 were selected.

Results

The five highest PS were seen with sneezing 290, irritation 238, running nose 228, stuffy nose 220, anxiety 203 and interrupted working 203. The 5 lowest PS were seen with disturbed sleep 83, dry throat 98, affected walking for 1/2 kilometre 98, do not sleep deeply 103 and phlegm 105.

Discussion

The five highest PS were due to symptoms of rhinitis, general irritation, anxiety & interruption of work. Thus rhinitis itself affects QOL. The 5 least PS were mainly sleep-related.

Conclusion

We have applied the MRQLQ on Indian patients with ARc. We could obtain a product score for every item in it, on the basis of which we could classify the degree of its effect on his QOL. PS was highest in rhinitis-related symptoms. 2 Emotions related and 1 Role limitation item gave moderate PS, while all PS in eye related, Physical functioning, Social functioning, Sleep-related & Other Symptoms items were in the mild range. Larger data sample is needed to validate and show its discriminatory power.     

Early intervention in developmental delay

Objectives: To establish the socio-demographic and clinical profile of children attending Early Intervention Program (EIP).Methods: Retrospective analysis of case records of 100 consecutive children examined from July 2002 to June 2004. Data regarding socio-demographic variables, clinical profile, locomotor, speech and audiology functions were recorded. Data is described in terms of frequency and mean (with SD).Results: Mean age of these children was 4.0±1.4 years. 70% were male and a similar percentage hailed from urban areas. 88% were mentally retarded with mean IQ of 50±24.3. Cerebral Palsy was seen in 50% of the children, learning disorder in 24%, Attention Deficit Hyperactivity Disorder (ADHD) in 12% and autism in 4%. 25% of children suffered from epilepsy and 66% were unable to communicate verbally. 21% of children had strong evidence of genetic disorders. An etiological diagnosis could not be made in 31% of children.Conclusions: Awareness of developmental delay as well as of possible interventions is low in India. Speech delay is the only delay which is considered important by parents. Active involvement and early referrals from pediatricians, obstetricians and other specialists is suggested.     

Susac syndrome in a young child

Susac syndrome is a microangiopathy of unknown origin affecting the brain, retina and inner ear. This rare entity is often misdiagnosed as a demyelinating condition such as multiple sclerosis or acute disseminated encephalomyelitis. A high index of suspicion must be present as the majority of patients do not have the complete clinical triad at the time of onset of symptoms. The radiologist plays an important role when the disease is suspected and helps orient the investigations. The syndrome has characteristic imaging features on MRI that include multifocal white matter and occasional grey matter lesions, the corpus callosum being always involved. The predominant central callosal lesions, especially with rapid cystic transformation (central callosal holes) can be considered pathognomonic of this condition in the appropriate clinical setting. This disease is extremely rare in children. We report a case of Susac syndrome in a 9-year-old girl to increase the awareness among paediatric radiologists of this entity, which is usually not considered as a differential diagnosis of multifocal white matter involvement in this age group.