MMP-9 Mediates Cross-Talk between Neutrophils and Endothelial Cells in Psoriasis

In their report, Chen et al. provide new insights into psoriasis pathogenesis, showing that neutrophil infiltration of skin lesions increases vascular endothelial cell (VEC) activation, leading to cutaneous vasodilation and enhanced vascular permeability. In patients with psoriasis, neutrophil-derived matrix metalloproteinase 9 (MMP-9) plays a pivotal role in VEC barrier dysfunction, via extracellular signal–regulated kinase-1/2 and p38 pathways. Pharmacologic inhibition of MMP-9 in two different models confers reduced cutaneous vasodilation, vascular permeability, and inflammation, suggesting MMP-9 as a target in psoriasis pathogenesis. In their report, Chen et al. provide new insights into psoriasis pathogenesis, showing that neutrophil infiltration of skin lesions increases vascular endothelial cell (VEC) activation, leading to cutaneous vasodilation and enhanced vascular permeability. In patients with psoriasis, neutrophil-derived matrix metalloproteinase 9 (MMP-9) plays a pivotal role in VEC barrier dysfunction, via extracellular signal–regulated kinase-1/2 and p38 pathways. Pharmacologic inhibition of MMP-9 in two different models confers reduced cutaneous vasodilation, vascular permeability, and inflammation, suggesting MMP-9 as a target in psoriasis pathogenesis. “There is a differential mechanism through which integrin α3 fosters tumor growth in basal versus suprabasal keratinocytes, engaging layer-specific binding partners.”Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes, infiltration of inflammatory cells, and neoangiogenesis (Boehncke and Schön, 2015Boehncke W.H. Schön M.P. Psoriasis.Lancet. 2015; 386: 983-994Abstract Full Text Full Text PDF PubMed Scopus (1355) Google Scholar). Although the precise etiology of the disease remains unclear, a combination of genetic and environmental factors is known to trigger abnormal immune-mediated responses involving the IL-23/IL-17 pathway. IL-17A primarily acts on keratinocytes, leading to the production of cytokines and chemokines, including TNF-α and CXCL-1/IL-8, that initiate neutrophil infiltration of skin (Martin et al., 2013Martin D.A. Towne J.E. Kricorian G. Klekotka P. Gudjonsson J.E. Krueger J.G. et al.The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings.J Invest Dermatol. 2013; 133: 17-26Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar). Recent studies have shown that infiltrated neutrophils might contribute to the pathogenesis of psoriasis by generating ROS and releasing neutrophil extracellular traps (NETs) (von Stebut et al., 2020von Stebut E. Boehncke W.H. Ghoreschi K. Gori T. Kaya Z. Thaci D. et al.IL-17A in psoriasis and beyond: cardiovascular and metabolic implications.Front Immunol. 2020; 10: 3096Crossref Scopus (79) Google Scholar). Notably, the therapeutic depletion of neutrophils significantly relieves the symptoms of patients with pustular psoriasis (Ikeda et al., 2013Ikeda S. Takahashi H. Suga Y. Eto H. Etoh T. Okuma K. et al.Therapeutic depletion of myeloid lineage leukocytes in patients with generalized pustular psoriasis indicates a major role for neutrophils in the immunopathogenesis of psoriasis.J Am Acad Dermatol. 2013; 68: 609-617Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). In their report, Chen et al., 2020Chen J. Zhu Z. Li Q. Lin Y. Dang E. Meng H. et al.Neutrophils enhance cutaneous vascular dilation and permeability to aggravate psoriasis by releasing matrix metallopeptidase 9.J Invest Dermatol. 2021; 141: 787-799Scopus (12) Google Scholar show that cross-talk between neutrophils and skin vascular endothelial cells (VECs) is important for psoriasis development. During the transendothelial migration process, neutrophils activate skin VECs, enhancing vasodilation and vascular permeability, which in turn enhances capillary transmigration of neutrophils and T lymphocytes into inflamed skin. Mechanistically, the authors showed that neutrophils derived from patients with psoriasis express several inflammatory mediators, including matrix metalloproteinase-9 (MMP-9), that play pivotal roles in VEC activation via extracellular signal–regulated kinase-1/2 (ERK-1/2) and p38 pathways, with reduced VE-cadherin– and F-actin–containing junctions. Consistent with these observations, pharmacologic inhibition of MMP-9 reduced cutaneous vasodilation, vascular permeability, inflammation, and psoriatic symptoms in imiquimod- or IL-23–induced psoriasiform mouse models. Thus, neutrophil-derived MMP-9 augments cutaneous vasodilation and protein leakage by activating skin VECs, thereby enhancing inflammation and psoriatic lesion development (Figure 1a ). However, whether or not MMP-9 inhibition affects primary functions of neutrophils such as ROS generation or NET formation and whether or not the IL-23/IL-17 pathway is involved in MMP-9 production by neutrophils remains to be determined in future studies. This study is of interest because it improves the mechanistic understanding of the role of neutrophils in the immunopathogenesis of psoriasis (Figure 1b) and may highlight a new therapeutic strategy for psoriasis treatment. José Carlos Alves-Filho: https://orcid.org/0000-0002-9918-8714 Bruno Marcel Silva Melo: https://orcid.org/0000-0001-7422-1445 Bernhard Ryffel: https://orcid.org/0000-0003-2897-8230 The authors state no conflict of interest. Neutrophils Enhance Cutaneous Vascular Dilation and Permeability to Aggravate Psoriasis by Releasing Matrix Metallopeptidase 9Journal of Investigative DermatologyVol. 141Issue 4PreviewNeutrophil infiltration and papillary vessel dilation are hallmarks of the initiation phase of psoriatic lesions. However, how neutrophils aggravate psoriasis development during transendothelial migration and the interaction between neutrophils and cutaneous vascular endothelial cells are less well-understood. In this study, we reported that neutrophils and cutaneous vascular endothelial cells activated each other when neutrophils migrated through the cutaneous endothelial barrier. In addition, neutrophil infiltration into skin lesions caused vascular remodeling including cutaneous vasodilation and enhanced vascular permeability in vivo and in vitro. Full-Text PDF Open Archive