AbstractBackgroundOrganisms have orchestrated coagulation and immune systems. Although a link between inflammation and haemostasis has been reported in asthma, the interaction mechanism has not been completely elucidated. Here, we investigated the direct link between the mammalian immune and coagulation systems.MethodsMice were administered protease or antigens intranasally to induce airway inflammation with or without thrombin inhibitors treatment. The effects of thrombin and its inhibitors on interleukin (IL)‐33 were investigated both in vivo and in vitro. Peripheral blood mononuclear cells (PBMCs) and plasma from asthma patients are collected to verify the correlation between thrombin and group 2 innate lymphocytes (ILC2s).ResultsLow‐molecular‐weight heparin (LMWH, an indirect inhibitor of thrombin) restrained both papain‐ and fungus‐induced type 2 immune responses in mice by inhibiting IL‐33 cleavage. Upon examining the potential thrombin protease consensus sites, we found that IL‐33 was directly cleaved by thrombin at specific amino acids (R48 and R106) to generate a mature form of IL‐33 with potent biological activity. In addition, we found that bivalirudin TFA (a direct inhibitor of thrombin) inhibited a variety of type 2 inflammatory responses, such as those in house dust mite (HDM)‐ and ovalbumin (OVA)‐mediated pulmonary inflammation models. We found that plasma thrombin‐antithrombin complex (TATc) levels in asthma patients were positively associated with the number and function of IL‐33‐responder group 2 innate lymphocytes (ILC2s) among peripheral blood mononuclear cells (PBMCs) from asthma patients.ConclusionThe data suggested that thrombin inhibitors administration could be effective in treating lung inflammation by regulating ILC2s via IL‐33 maturation, indicating that targeting thrombin is a potential way to treat allergic diseases.