The Antimicrobial Cathelicidin CRAMP Augments Platelet Activation during Psoriasis in Mice

Abstract

Platelet-associated complications including thrombosis, thrombocytopenia, and haemorrhage are commonly observed during various inflammatory diseases such as psoriasis. Although several mechanisms that may contribute to the dysfunction of platelets during inflammatory diseases have been reported, knowledge on the primary molecules/mechanisms that underpin platelet-associated complications in such conditions is not fully established. Here, we report the significance of the mouse antimicrobial cathelicidin, mouse cathelicidin-related antimicrobial peptide (mCRAMP) (an orthologue of LL37 in humans), on the modulation of platelet reactivity during psoriasis using Imiquimod-induced psoriasis in mice as an inflammatory disease model for psoriasis vulgaris in humans. The activation of platelets during psoriasis is increased as evidenced by the elevated levels of fibrinogen binding and P-selectin exposure on the surface of platelets, and the level of soluble P-selectin in the plasma of psoriatic mice. The skin and plasma of psoriatic mice displayed increased levels of mCRAMP. Moreover, the plasma of psoriatic mice augmented the activation of platelets obtained from healthy mice. The effect of mCRAMP is partially mediated through formyl peptide receptor 2/3 (Fpr2/3, the orthologue to human FPR2/ALX) in platelets as a significant reduction in their activation was observed when FPR2/ALX-selective inhibitors such as WRW4 or Fpr2/3-deficient mouse platelets were used in these assays. Since the level of antimicrobial cathelicidin is increased in numerous inflammatory diseases such as psoriasis, atherosclerosis, and inflammatory bowel disease, the results of this study point towards a critical role for antimicrobial cathelicidin and FPR2/ALX in the development of platelet-related complications in such diseases.

Hyperforin Ameliorates Imiquimod-Induced Psoriasis-Like Murine Skin Inflammation by Modulating IL-17A–Producing γδ T Cells

“…Recently, antimicrobial peptides and proteins (AMPs) such as cathelicidin, β-defensins, and S100 proteins, secreted by keratinocytes are inferred to be related with severity of psoriasis lesions ( 21 ), and excessive production of AMPs are widely confirmed in psoriasis lesions ( 21 – 23 ). Previous studies have indicated that imiquimod increase the production of AMPs ( 24 – 26 ). Therefore, our experiments were exerted to demonstrate the effect of hyperforin on the expression of AMPs.…”

Deletion of Annexin A1 in Mice Upregulates the Expression of Its Receptor, Fpr2/3, and Reactivity to the AnxA1 Mimetic Peptide in Platelets

“…While the modulatory effects of ANXA1 and ANXA1 Ac2-26 during inflammation have been extensively studied in numerous disease models, their importance in platelet-mediated thromboinflammation is not yet fully understood. Recently, we reported the significance of FPRs and some of their ligands such as an antimicrobial peptide, LL37 [ 20 , 21 ], and a bacterial formyl peptide, fMLF [ 22 ], in the regulation of platelet function. Due to the critical roles of platelets at the interface between thrombosis and inflammation [ 3 ], the detailed characterisation of inflammatory receptors such as FPR2/ALX will pave the way to the development of novel therapeutic strategies to control exacerbated thromboinflammatory responses during pathological conditions.…”

Impaired tolerance to the autoantigen LL-37 in acute coronary syndrome

“…However, autoimmune patients have impaired tolerance and are at higher risk for developing cardiovascular disease ( 44 ) suggesting potentially shared pathophysiology. Among the self-antigens of interest, we focused our work on LL-37, a T cell autoantigen in psoriasis and SLE ( 11 – 14 ), that plays a role in innate immune responses as damage-associated molecular pattern (DAMP) ( 45 ) as well as its participation in thrombus formation ( 19 ), both key elements of ACS. Increased LL-37 expression by intermediate monocytes in single-cell RNA sequencing assay of PBMCs was recently demonstrated in acute MI ( 2 ).…”

“…It is a component of neutrophil extracellular traps (NETs) that are implicated in atherogenesis ( 16 , 17 ). In addition, NET burden is associated with infarct size in ST segment elevation myocardial infarction (STEMI) ( 18 ) while LL-37 is associated with platelet activation and thrombosis ( 19 ). LL-37 is an immune modulator that has HLA-specific or adjuvant effects on the immune response ( 11 , 20 ).…”