Ahmed Shah1, Raed Alhusayen1,2,3, Saeid Amini-Nik4,5,6,7. 1. Faculty of Medicine, University of Toronto, Toronto, Canada. 2. Division of Dermatology, University of Toronto, Toronto, Canada. 3. Sunnybrook Health Science Center, Sunnybrook Research Institute, Toronto, Canada. 4. Faculty of Medicine, University of Toronto, Toronto, Canada. saeid.amininik@utoronto.ca. 5. Department of Surgery, University of Toronto, Toronto, Canada. saeid.amininik@utoronto.ca. 6. Department of Laboratory Medicine and Pathobiology (LMP), University of Toronto, Toronto, Canada. saeid.amininik@utoronto.ca. 7. Sunnybrook Health Science Center, Sunnybrook Research Institute, Toronto, Canada. saeid.amininik@utoronto.ca.
Abstract
INTRODUCTION: Hidradenitis suppurativa (HS) is a painful chronic inflammatory disease with a prevalence between 1 and 4% of general population. The pathogenesis of HS long eluded scientists, but growing evidence suggests that it is a consequence of inflammatory dysregulation. FINDINGS: Recent studies suggest that dysregulated immune response to skin flora and overexpression of inflammatory cytokines leads to chronic skin inflammation seen in HS. Macrophages are the most numerous inflammatory cells found in HS infiltrates and release numerous pro-inflammatory cytokines such as IL-23, and IL-1β and TNF-α, exacerbating the inflammation and contributing to the pathogenesis of HS. Furthermore, in HS, there is dysregulated function of other immune players closely associated with macrophage function including: matrix metalloproteases (MMP) 2 and 9 overexpression, toll-like receptor upregulation, impaired Notch signalling, NLRP3 inflammasome upregulation, and dysregulated keratinocyte function. Lifestyle factors including obesity and smoking also contribute to macrophage dysfunction and correlate with HS incidence. CONCLUSIONS: The overexpression of pro-inflammatory cytokines and subsequent efficacy of anti-cytokine biologic therapies highlights the importance of managing macrophage dysfunction. Future therapies should target key molecular drivers of macrophage dysfunction such as TLR2 and NLRP3 overexpression.
INTRODUCTION:Hidradenitis suppurativa (HS) is a painful chronic inflammatory disease with a prevalence between 1 and 4% of general population. The pathogenesis of HS long eluded scientists, but growing evidence suggests that it is a consequence of inflammatory dysregulation. FINDINGS: Recent studies suggest that dysregulated immune response to skin flora and overexpression of inflammatory cytokines leads to chronic skin inflammation seen in HS. Macrophages are the most numerous inflammatory cells found in HS infiltrates and release numerous pro-inflammatory cytokines such as IL-23, and IL-1β and TNF-α, exacerbating the inflammation and contributing to the pathogenesis of HS. Furthermore, in HS, there is dysregulated function of other immune players closely associated with macrophage function including: matrix metalloproteases (MMP) 2 and 9 overexpression, toll-like receptor upregulation, impaired Notch signalling, NLRP3 inflammasome upregulation, and dysregulated keratinocyte function. Lifestyle factors including obesity and smoking also contribute to macrophage dysfunction and correlate with HS incidence. CONCLUSIONS: The overexpression of pro-inflammatory cytokines and subsequent efficacy of anti-cytokine biologic therapies highlights the importance of managing macrophage dysfunction. Future therapies should target key molecular drivers of macrophage dysfunction such as TLR2 and NLRP3 overexpression.
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