Innate lymphoid cells are double‐edged swords under the mucosal barrier

Abstract As the direct contacting site for pathogens and allergens, the mucosal barrier plays a vital role in the lungs and intestines. Innate lymphoid cells (ILCs) are particularly resident in the mucosal barrier and participate in several pathophysiological processes, such as maintaining or disrupting barrier integrity, preventing various pathogenic invasions. In the pulmonary mucosae, ILCs sometimes aggravate inflammation and mucus hypersecretion but restore airway epithelial integrity and maintain lung tissue homeostasis at other times. In the intestinal mucosae, ILCs can increase epithelial permeability, leading to severe intestinal inflammation on the one hand, and assist mucosal barrier in resisting bacterial invasion on the other hand. In this review, we will illustrate the positive and negative roles of ILCs in mucosal barrier immunity.

damaged mucosal-derived 'risk signals' sensitively and quickly due to the close proximity of the damaged site, triggering ILC-mediated subsequent inflammatory response and tissue repair. Significant attention is paid to the role of ILCs that may also be of great therapeutic potential in mucosal diseases. In this review, we focus on the physiological and pathological functions of ILCs in the mucosal barrier. Meanwhile, we summarize the positive and negative roles of ILCs in mucosal barrier immunity. When external irritations stimulate mucosae, ILCs play a positive role to maintain mucosal homeostasis by alleviating inflammation and promoting tissue repair.
However, excessive ILCs can also play a negative role by recruiting inflammatory cells and pro-inflammatory cytokines, leading to damage the integrity of mucosae and accelerate the pathological process of chronic mucosal diseases.

| MUCOSAL BARRIER AC TS MORE THAN A PHYS I C AL BARRIER
The mucosal barrier is the first site to contact with the environmental antigens and pathogens, such as viruses, fungi, parasites and bacteria. The intact epithelia, cilia and mucus together constitute a strong physical barrier against external stimulus. A variety of allergens and stimuli, except probiotics, are detrimental to the host.
After prolonged and/or extensive exposure to ozone, house dust mite (HDM), bacteria and viruses, etc., epithelial structural proteins such as E-cadherin and zonula occludens-1 (ZO-1) were destructed, resulting in decreased epithelial tightness and barrier damage. [1][2][3][4] The dysfunction of epithelia is a common pathological characteristic of mucosal diseases. Various degrees of epithelial damage are the key determinant of mucosal diseases such as asthma, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (IBD) and the degree of epithelial damage is positively correlated with the severity of diseases. [5][6][7] Once the mucosal system is too vulnerable to identify and/or eliminate noxious stimuli in time, pathogen-induced inflammation may damage the mucosal barrier excessively, leading to severe infection, cytokine storm or even death eventually. [8][9][10][11] The mucosal system can be involved in many mucosal diseases in addition to its physical barrier function. More importantly, it also has a powerful immune function. When the structure and function of the mucosal barrier are damaged, mucosal epithelia would secret cytokines and inflammatory mediators to trigger systemic immune response and eliminate pathogens, which in turn restore the homeostasis of the mucosal barrier. 12,13 In the process of mucosal immune response, ILCs have attracted a substantial amount of attention due to special distribution and function. A large number of studies have demonstrated that the activation and differentiation of ILCs have great biological significance in regulating local inflammation and promoting tissue repair in the mucosal barrier. The distribution and function of ILCs in the mucosal barrier and the involvement of ILCs in mucosal diseases deserve further study.

| PROFILE OF ILC S
In recent years, ILCs have aroused broad attention in the mucosal immunity and the homeostasis of mucosal barrier. ILCs are renewed from progenitors, and recent studies have identified that CD117 + ILC precursors derived from CD34 + hematopoietic stem cells can generate almost all mature ILC subsets (except for interleukin-17A + ILC3s) under appropriate environmental signals. 14,15 Interestingly, CD117 + ILC precursors can circulate in the peripheral blood or reside in the tissues, but lineage-specified progenitors of ILC3s can be detected in tonsil and intestinal lamina propria but not in peripheral blood. 16 Of note, ILCs are sentinel cells distributed widely in the mucosal barrier, while most mature ILCs are resident in intestine lamina propria, lung and liver. 17 As ILCs are similar to T cells in terms of transcription and function, there are ILC subsets such as ILC1, ILC2, ILC3 and ILCreg by reference to the subsets of T cells (Table 1). [18][19][20] ILCs are developed and expanded within peripheral organs, and then acute infections or tissue damage rapidly triggers ILC precursors to differentiate into mature ILCs following cytokine-driven expansion. 21,22 ILCs do not express antigen-specific receptors, and cytokines are considered as powerful activators of ILCs. ILCs can directly respond to epithelial cytokines in the absence of T cells and even respond to 'risk signal' faster than T cells. [23][24][25] Furthermore, ILC2s activated by IL-33 may produce 10 times more type 2 cytokines than Th2 cells do. 26 ILCs are involved in the first-line immune defence by secret- NK cells. 27 Besides, IL-25 can induce ILC2s to produce IL-5 and IL-13 even in RAG-deficient mice. 28 Intriguingly, there are a series of IL-10-secreting ILCs, generated in severe inflammatory environment, which in turn alleviate inflammation in different ways. [29][30][31] It is revealed that the interaction between inflammatory factors and IL-10-secreting ILCs may initiate tissue damage repair, which may constitute a negative feedback system to guard the mucosal immune system and the homeostasis of mucosae.
The interaction between cytokines and ILCs is intricate and complex. The differentiation and function of ILCs can also be regulated by cytokines in local microenvironment. [32][33][34] In the complex mucosal environment, ILCs are heterogeneous and highly plastic. To sum up, ILCs are abundant in mucosal barrier, close to the damaged site, and can respond to inflammatory signal sensitively.
Particularly, ILCs are of typical plasticity, which indicates that ILCs may function as a double-edged sword in mucosal barrier. The various characteristics of ILCs indicate that they have great potential in mucosal diseases. We will elucidate how ILCs regulate the immune responses and maintain the homeostasis of mucosal barriers involving lungs and intestines.

| ILC S IN THE LUNG S
As a tissue directly contacting the external environment, lung mucosae need to cope with airborne dust, pollen, ozone, microbes, etc.
Submucosal ILCs are essential for the integrity and homeostasis of the lung mucosal barrier. Upon sensing the 'risk signal' from damaged mucosal epithelia, ILCs will proliferate, activate and release various cytokines to respond to harmful environmental components promptly and appropriately. Non-recirculating ILCs in the lungs con-   50 Furthermore, given that IL-17A is a detrimental factor to COPD, IL-17-secreting ILC3s may also participate in the pathology of COPD. 51 The exacerbation of COPD is associated with ILC1s, while the lung functionality of asthma patients is closely related to ILC2s. 52 The frequency of ILC2s is increased in allergic asthma patients, which are sufficient to initiate asthma. 53 70 In addition, IL-17producing ILC3s promote AHR in obesity-associated asthma. 71,72 Except for COPD and asthma, several studies have revealed that ILC2s are involved in the pathogenesis of chronic rhinosinusitis with nasal polyps and idiopathic pulmonary fibrosis. 73,74 There is no doubt ILC-regulated mucosal immunity is of great significance to lung defence and chronic diseases. A proper ILCmediated defence is very beneficial to the homeostasis of lung.
However, when lung mucosae are severely damaged or in a state of long-term damage, ILCs will lead to the development of chronic pulmonary diseases. Notably, different subtypes of ILCs have different effects on the outcome of lung disease. How ILCs function in different environments and the role of ILCs plasticity in chronic diseases still need further study. Particularly, the investigation about the activation and function of ILC3s in lung mucosae is relatively rare. Besides, infections with extracellular bacteria and fungi are lack of concern in ILC-regulated lung immunity. In-depth studies on resident ILCs in the lungs are expected to provide new perspective to the treatment of these pulmonary diseases.

| ILC S IN THE INTE S TINE S
The intestines must process a large amount of food every day and

ACK N OWLED G M ENTS
I would like to express my gratitude to all those who helped me during the writing of this review, and I deeply appreciate the contribution to this review made by them.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.