Background: The interaction of coagulation factors has been shown to go beyond their traditional roles in hemostasis and to affect the development of inflammatory diseases. Key molecular players, such as fibrinogen, thrombin, or factor XII have been mechanistically and epidemiologically linked to inflammatory disorders like multiple sclerosis (MS), rheumatoid arthritis (RA), and colitis. Objectives: To systematically review the evidence for a role of coagulation factors, especially factor XII, fibrinogen, and thrombin in inflammatory disorders like MS, RA, and bowel disorders. Methods: A systematic literature search was done in the PubMed database to identify studies about coagulation factors in inflammatory diseases. Original articles and reviews investigating the role of the kallikrein–kinin and the coagulation system in mouse and humans were included. Results: We identified 43 animal studies dealing with inflammatory disorders and factors of the kallikrein–kinin or the coagulation system. Different immunological influences are described and novel molecular mechanisms linking coagulation and inflammation are reported. Conclusion: A number of studies have highlighted coagulation factors to tip the balance between hemostasis and thrombosis and between protection from infection and extensive inflammation. To optimize the treatment of chronic inflammatory disorders by these factors, further studies are necessary.

Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.

Multiple sclerosis (MS) is a common neurological disorder of putative autoimmune origin. Clinical studies delineate abnormal expression of specific cytokines over the course of disease. Preclinical studies using animal models of MS have yielded promising results in manipulating the activity of certain cytokines to improve the clinical outcome. However, the translation of these findings into the clinic is often disappointing. The reason for this might be the complex nature of cytokine networks and the pathogenesis of neuroinflammation, as well as an oversimplified interpretation of preclinical observations. This review presents an overview on cytokines that potentially contribute to the development of MS and provides examples of success and failure in translating basic science into clinical benefit for people with MS.

Significance: Transendothelial trafficking of immune cells into the central nervous system (CNS) is a pathophysiological hallmark of neuroinflammatory disorders like multiple sclerosis (MS). Recent evidence suggests that the coagulation and kallikrein-kinin cascade might participate in this process. Here, we identify plasma kallikrein (KK) as a direct modulator of blood–brain barrier function in a protease-activated receptor-2–dependent manner, amplifying leukocyte trafficking into the CNS. Consequently, a deficiency of plasma prekallikrein (PK), the precursor of KK, renders mice less susceptible to experimental autoimmune encephalomyelitis (model of MS). Furthermore, PK levels were markedly enhanced in CNS lesions of MS patients. In summary, our study indicates that KK inhibition can decrease cell invasion during neuroinflammation and may offer a strategy to combat MS.

Background and Purpose: The existence of functional K_v7 channels in thalamocortical (TC) relay neurons and the effects of the K⁺‐current termed M‐current (I_M) on thalamic signal processing have long been debated. Immunocytochemical evidence suggests their presence in this brain region. Therefore, we aimed to verify their existence, pharmacological properties and function in regulating activity in neurons of the ventrobasal thalamus (VB).Experimental Approach: Characterization of K_v7 channels was performed by combining in vitro, in vivo and in silico techniques with a pharmacological approach. Retigabine (30 μM) and XE991 (20 μM), a specific K_v7 channel enhancer and blocker, respectively, were applied in acute brain slices during electrophysiological recordings. The effects of intrathalamic injection of retigabine (3 mM, 300 nL) and/or XE991 (2 mM, 300 nL) were investigated in freely moving animals during hot‐plate tests by recording behaviour and neuronal activity.Key Results: K_v7.2 and K_v7.3 subunits were found to be abundantly expressed in TC neurons of mouse VB. A slow K⁺‐current with properties of I_M was activated by retigabine and inhibited by XE991. K_v7 channel activation evoked membrane hyperpolarization, a reduction in tonic action potential firing, and increased burst firing in vitro and in computational models. Single‐unit recordings and pharmacological intervention demonstrated a specific burst‐firing increase upon I_M activation in vivo. A K_v7 channel‐mediated increase in pain threshold was associated with fewer VB units responding to noxious stimuli, and increased burst firing in responsive neurons.Conclusions and Implications: K_v7 channel enhancement alters somatosensory activity and may reflect an anti‐nociceptive mechanism during acute pain processing.