HMGB1-Directed Drug Discovery Targeting Cutaneous Inflammatory Dysregulation

Abstract

Extracellular cytokine function of the non-histone nuclear protein high-mobility group box 1 (HMGB1) has recently been recognized as an important drug target for novel anti-inflammatory therapeutics. Accumulating evidence supports the mechanistic involvement of the alarmin HMGB1 in skin response to microbial infection and ultraviolet-induced solar damage. Moreover, HMGB1 modulation of inflammatory signaling and tissue remodeling is now emerging as a causative factor in wound repair, autoimmune dysregulation, and skin carcinogenesis, representing cutaneous pathologies that affect large patient populations with unmet therapeutic needs. Recent structure-based drug discovery efforts have aimed at increasing the number of small molecule- and biologics-based prototype therapeutics targeting HMGB1. Small molecule drugs that may provide therapeutic benefit through HMGB1-directed mechanisms involve HMGB1 inhibitory ligands, Toll-like receptor antagonists, RAGE antagonists, alpha7 nicotinic acetylcholine receptor agonists, G2A antagonists, serine protease inhibitors, and alpha-dicarbonyl-based soft electrophiles. Using some of these agents, pharmacological modulation of HMGB1-associated cutaneous pathology has been achieved with an acceptable toxicity profile, and preclinical proof-of-concept experimentation has demonstrated feasibility of developing HMGB1-modulators into novel systemic and topical therapeutics that target cutaneous inflammatory dysregulation.

ALK+ALCLs induce cutaneous, HMGB-1–dependent IL-8/CXCL8 production by keratinocytes through NF-κB activation

“…On a grander scale, HMGB-1 modulation of inflammatory signaling is emerging as a causative factor for skin carcinogenesis. 41 The results of the present study suggest that Figure 6. HMGB-1, IL-8, and IL-8 receptor (CXCR1 and CXCR2) expression by ALK ؉ ALCL patients.…”

“…On a grander scale, HMGB-1 modulation of inflammatory signaling is emerging as a causative factor for skin carcinogenesis. 41 The results of the present study suggest that the pro-inflammatory cytokine HMGB-1 released from ALK ϩ lymphoma cells could create a premetastatic niche into the skin. This epidermal inflammatory environment would then contribute to ALK ϩ tumor cell recruitment and favor the development of metastasis within the skin.…”

Genomic Analysis and Differential Expression of HMG and S100A Family in Human Arthritis: Upregulated Expression of Chemokines, IL-8 and Nitric Oxide by HMGB1

“…A drug such as Atrovastatin (Lipitor) reduces increased levels of hyperlipidemia and HMGB1 in the serum ( Jin et al, 2012). Therapeutic benefits through HMGB1-directed mechanisms involve HMGB1 inhibitory ligands such as Toll-like receptor antagonists, RAGE antagonists, and alpha7 nicotinic acetylcholine receptor agonists (Lamore et al, 2010). Antibodies that neutralize HMGB1 are known to confer protection against tissue damage and injury in joints Sparvero et al, 2009).…”

TLR4 in skin cancer: From molecular mechanisms to clinical interventions

“…TLR4 has now been recognized as an important determinant of skin barrier function with specific roles in wound healing, tissue remodeling, and innate immunity. Consistent with these physiological roles, it has also been shown that signaling through keratinocyte‐derived HMGB1 and TLR4 represents an important factor underlying skin inflammation . TLR4 involvement has now been implicated in numerous skin pathologies, including atopic dermatitis and psoriasis .…”

“…TLR4 expression in cutaneous antigen‐presenting cells and keratinocytes is upregulated and activated in response to UV . TLR4 also responds to endogenous ligands (eg, HMGB1) released in an autocrine fashion from keratinocytes as a consequence of cytotoxic environmental stress including solar UV . Blocking cutaneous HMGB1 reduces inflammatory cytokine production and inflammatory cell recruitment .…”