The chitinase-like protein Ym2 is an amplifier of innate type 2 responses

Regulation of innate immunity in the lung is poorly understood. In mice, the chitinase-like proteins Ym1 and Ym2 are highly upregulated in an IL-4/IL-13-dependent manner, making them prominent components of type 2-dependent processes. However, despite the strong association with type 2 immunity, their exact biological roles in type 2 pathologies like asthma are still largely elusive. In this study, we took a reductionist approach and treated wild-type mice with classical innate type 2 cytokines (IL-25, IL-33 or TSLP), either alone or in combination with Ym2. These so-called alarmins initiate and maintain local type 2 responses in the lung, mainly through the expansion of IL-13-secreting lung-resident innate lymphoid cells (ILC2). A sub-optimal dose of these cytokines only induced a modest type 2 response. Strikingly, co-administration with Ym2 strongly amplified allergic inflammation, resulting in increased eosinophils, IL-13-producing ILC2 and IL-5/13 concentration in the airways. Similarly, Ym2 also significantly synergised with IL-33 in vitro to boost type 2 cytokines from ILC2, such as IL-9, a crucial autocrine amplifier of ILC2 function and survival. To further delineate the role of endogenous Ym2 in regulating type 2 inflammation in vivo, we analysed ILC activation in newly generated Ym2-deficient mice. Following IL-33 administration, the frequency of ILC2s, as well as IL-5/13 concentration in the airways were reduced in Ym2-deficient compared to wild-type mice, demonstrating that endogenous Ym2 promotes ILC2 activation and effector function. In summary, these data show that Ym2 is necessary and sufficient to boost the proinflammatory role of type 2 alarmins leading to expansion of inflammatory ILC2.