Neutrophils Self-Regulate Immune Complex-Mediated Cutaneous Inflammation through CXCL2
Division of Dermatology, Department of Medicine; UMass Metabolic Network
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Dermatology | Immunology and Infectious Disease | Molecular Biology
Deposition of immune complexes (ICs) in tissues triggers acute inflammatory pathology characterized by massive neutrophil influx leading to edema and hemorrhage, and is especially associated with vasculitis of the skin, but the mechanisms that regulate this type III hypersensitivity process remain poorly understood. Here, using a combination of multiphoton intravital microscopy and genomic approaches, we re-examined the cutaneous reverse passive Arthus reaction and observed that IC-activated neutrophils underwent transmigration, triggered further IC formation, and transported these ICs into the interstitium, whereas neutrophil depletion drastically reduced IC formation and ameliorated vascular leakage in vivo. Thereafter, we show that these neutrophils expressed high levels of CXCL2, which further amplified neutrophil recruitment and activation in an autocrine and/or paracrine manner. Notably, CXCL1 expression was restricted to tissue-resident cell types, but IC-activated neutrophils may also indirectly, via soluble factors, modulate macrophage CXCL1 expression. Consistent with their distinct cellular origins and localization, only neutralization of CXCL2 but not CXCL1 in the interstitium effectively reduced neutrophil recruitment. In summary, our study establishes that neutrophils are able to self-regulate their own recruitment and responses during IC-mediated inflammation through a CXCL2-driven feed forward loop.
DOI of Published Version
J Invest Dermatol. 2016 Feb;136(2):416-24. doi: 10.1038/JID.2015.410. Link to article on publisher's site
The Journal of investigative dermatology
Li, Jackson LiangYao; Harris, John E.; and Ng, Lai Guan, "Neutrophils Self-Regulate Immune Complex-Mediated Cutaneous Inflammation through CXCL2" (2016). UMass Metabolic Network Publications. 58.