SHP-1 and IL-1α conspire to provoke neutrophilic dermatoses

Abstract

Neutrophilic dermatoses are a spectrum of autoinflammatory skin disorders that are characterized by extensive infiltration of neutrophils into the epidermis and dermis. The underlining biological pathways that are responsible for this heterogeneous group of cutaneous diseases have remained elusive. However, recent work from our laboratory and other groups has shown that missense mutations in Ptpn6, which encodes for the non-receptor protein tyrosine phosphatase Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1), results in a skin disease with many of the major histopathological and clinical features that encompass neutrophilic dermatoses in humans. In particular, we found that loss-of-function mutation in Ptpn6 results in unremitting footpad swelling, suppurative inflammation, and neutrophilia. Dysregulated wound healing responses were discovered to contribute to chronic inflammatory skin disease in SHP-1 defective mice and genetic abrogation of interleukin-1 receptor (IL-1R) protected mice from cutaneous inflammation, suggesting that IL-1-mediated events potentiate disease. Surprisingly, inflammasome activation and IL-1β-mediated events were dispensable for Ptpn6spin-mediated footpad disease. Instead, RIP1-mediated regulation of IL-1α was identified to be the major driver of inflammation and tissue damage.

Distinct role of IL-1β in instigating disease in Sharpincpdm mice

“…Cell death pathways involving TNFR, caspase-8, FADD, RIPK3, and RIPK1 are all involved in the disease progression of Sharpin cpdm mice3. Because IL-1α is released following cell death and plays an important role in the skin inflammation observed in a mouse model of neutrophilic dermatoses31, we proposed that IL-1α would have a major role in driving the disease in Sharpin cpdm mice. However, IL-1α deficiency did not provide any protection from dermatitis or systemic inflammation in Sharpin cpdm mice.…”

Emerging Roles for the Immune System in Traumatic Brain Injury

“…In contrast, IL-1β is generated as a biologically inactive pro-form protein that requires cleavage to elicit its inflammatory properties and secretion (64). Caspase-1 activation in inflammasome complexes has emerged as a major mechanism for both IL-1β cleavage and IL-1α release (14, 65–69), although recent studies have also begun to identify additional inflammasome-independent pathways that promote IL-1 production (64, 70–72). …”

The Role of Interleukin-1 in Inflammatory and Malignant Human Skin Diseases and the Rationale for Targeting Interleukin-1 Alpha

“…In Ptpn6 mutant mice, which are SHP‐1 (Src homology region 2 [SH2] domain containing phosphatase 1) defective, the dysregulated IL‐1 levels were shown to trigger the development of autoinflammatory diseases and neutrophilic dermatosis (ND). In these mice, the activation of IL‐1RI, mainly via IL‐1α, is thought to be the inflammatory stimulant for the neutrophil infiltration to the site of damage . IL‐1α produced by both KCs and neutrophils induces autocrine and juxtacrine (neutrophil, DCs, …) functions and augments the levels of IL‐1α .…”

“…Inflammation/pathery 191,193,198,199 Neutrophil infiltration c, [192][193][194] Initiation of inflammation 219 Infiltration of neutrophils 219 Activation of inflammatory cascades b, 199,224 Continued DNA damage [225][226][227] Epidermal atypia 253,254 Ligand-independent receptor activation 105,226,230,231 Expression of proliferation and inflammation-inducing genes 232,[236][237][238][239] Premalignant lesions that can evolve to carcinoma (AK, BD) 276,277 Mutation of signaling molecules d,…”

“…In these mice, the activation of IL-1RI, mainly via IL-1α, is thought to be the inflammatory stimulant for the neutrophil infiltration to the site of damage. 219 IL-1α produced by both KCs and neutrophils induces autocrine and juxtacrine (neutrophil, DCs, . .…”