Cathelicidin‐related antimicrobial peptide (CRAMP) is an effector molecule of the innate immune system with direct antimicrobial and immunomodulatory activities; however, its role in neuroinflammatory responses and related diseases is not clearly understood. In particular, the expression of CRAMP and its functional role has not been previously studied in experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Here, we investigated the role of CRAMP in neuroinflammation, using an EAE mouse model of MS and postmortem patient tissues. We found that the CRAMP expression was increased in the spinal cords of EAE‐induced mice. Immunofluorescence analysis revealed that CRAMP is mainly induced in reactive astrocytes in the inflamed spinal cord of EAE mice. A similar pattern of the LL‐37 (human CRAMP) expression was observed in the brain and spinal cord tissues of patients with MS. An intrathecal injection of the CRAMP peptide in EAE mice accelerated the onset of symptoms and increased disease severity with augmented expression of inflammatory mediators, glial activation, infiltration of inflammatory cells, and demyelination. In addition, shRNA‐mediated knockdown of Cramp in the spinal cord resulted in a milder disease course with less inflammation in EAE mice. We identified FPR2 on microglia as a CRAMP receptor and demonstrated that CRAMP potentiates IFN‐γ‐induced microglial activation via the STAT3 pathway. Taken together, our findings suggest that CRAMP is a novel mediator of astrocyte–microglia interactions in neuroinflammatory conditions such as EAE. Thus, CRAMP could be exploited as a biomarker or therapeutic target for the diagnosis or treatment of MS.

Cathelicidin‐related antimicrobial peptide promotes neuroinflammation through astrocyte–microglia communication in experimental autoimmune encephalomyelitis

LXA4 inhibits TGF-β1-induced airway smooth muscle cells proliferation and migration by suppressing the Smad/YAP pathway.

AZ2158 is a more potent formyl peptide receptor 1 inhibitor than the commonly used peptide antagonists in abolishing neutrophil chemotaxis.

HCH6-1, an antagonist of formyl peptide receptor-1, exerts anti-neuroinflammatory and neuroprotective effects in cellular and animal models of Parkinson's disease.

Focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) show persistent neuroinflammation, which promotes epileptogenesis and epilepsy progression, suggesting that endogenous resolution of inflammation is inadequate to relieve neuronal network hyperexcitability. To explore the potential roles of formyl peptide receptor 2 (FPR2), which is a key regulator of inflammation resolution, in epilepsy caused by FCDIIb and TSC, we examined the expression and cellular distribution of FPR2.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/iid3.706

Downregulated formyl peptide receptor 2 expression in the epileptogenic foci of patients with focal cortical dysplasia type IIb and tuberous sclerosis complex

Formyl peptide receptors (FPRs) are a group of G protein-coupled cell surface receptors that play important roles in host defense and inflammation. Owing to the ubiquitous expression of FPRs throughout different cell types and since they interact with structurally diverse chemotactic agonists, they have a dual function in inflammatory processes, depending on binding with different ligands so that accelerate or inhibit key intracellular kinase-based regulatory pathways. Neuroinflammation is closely associated with the pathogenesis of neurodegenerative diseases, neurogenic tumors and cerebrovascular diseases. From recent studies, it is clear that FPRs are important biomarkers for neurological diseases as they regulate inflammatory responses by monitoring glial activation, accelerating neural differentiation, regulating angiogenesis, and controlling blood brain barrier (BBB) permeability, thereby affecting neurological disease progression. Given the complex mechanisms of neurological diseases and the difficulty of healing, we are eager to find new and effective therapeutic targets. Here, we review recent research about various mechanisms of the effects generated after FPR binding to different ligands, role of FPRs in neuroinflammation as well as the development and prognosis of neurological diseases. We summarize that the FPR family has dual inflammatory functional properties in central nervous system. Emphasizing that FPR2 acts as a key molecule that mediates the active resolution of inflammation, which binds with corresponding receptors to reduce the expression and activation of pro-inflammatory composition, govern the transport of immune cells to inflammatory tissues, and restore the integrity of the BBB. Concurrently, FPR1 is essentially related to angiogenesis, cell proliferation and neurogenesis. Thus, treatment with FPRs-modulation may be effective for neurological diseases.

/pdf/the-role-of-formyl-peptide-receptors-in-neurological-4nvndx0bz5.pdf

The Role of Formyl Peptide Receptors in Neurological Diseases via Regulating Inflammation.

Objective: We performed this study to investigate whether the EDNRA gene rs1878406 C > T polymorphism is associated with risk of large artery atherosclerosis (LAA) stroke in the Chinese Han population. Methods: Genotyping of rs1878406 was performed in 1,112 LAA stroke patients and 1,192 healthy controls. Multivariate logistic regression analyses were applied to assess the effect of the rs1878406 C > T polymorphism on susceptibility to LAA stroke. Results: A significant increase of LAA stroke risk was found in the recessive model (TT vs. CC/TC, OR = 1.74, 95% CI = 1.23–2.48, p = 0.002) and co-dominant model (TC vs. CC, OR = 1.06, 95% CI = 0.89–1.27, TT vs. CC, OR = 1.79, 95% CI = 1.25–2.55, p = 0.006). However, the interaction between age and genotypes of rs1878406 was not statistically significant, and no significant interactive effect was observed between the rs1878406 C > T polymorphism and sex (p > 0.05). Conclusion: The rs1878406 C > T polymorphism is associated with increased risk of LAA stroke in the Chinese Han population.

/pdf/ednra-gene-rs1878406-polymorphism-is-associated-with-25zfyba9.pdf

EDNRA Gene rs1878406 Polymorphism is Associated With Susceptibility to Large Artery Atherosclerotic Stroke

Cyclic GMP–AMP synthase (cGAS), a crucial innate immune sensor, recognizes cytosolic DNA and induces stimulator of interferon genes (STING) to produce type I interferon and other proinflammatory cytokines, thereby mediating innate immune signaling. The cGAS–STING pathway is involved in the regulation of infectious diseases, anti-tumor immunity, and autoimmune diseases; in addition, it plays a key role in the development of central nervous system (CNS) diseases. Therapeutics targeting the modulation of cGAS–STING have promising clinical applications. Here, we summarize the cGAS–STING signaling mechanism and the recent research on its role in CNS diseases.

Jiao Ding

Papers

The Role of Formyl Peptide Receptors in Neurological Diseases via Regulating Inflammation.

EDNRA Gene rs1878406 Polymorphism is Associated With Susceptibility to Large Artery Atherosclerotic Stroke

Research advances in cGAS–stimulator of interferon genes pathway and central nervous system diseases: Focus on new therapeutic approaches