TABLE 1.

Clinical and experimental studies defining the roles of IL‐25/IL‐33/TSLP on IPF

Ref.	Authors	Study design	Major findings	Conclusions
IL‐25
22	Hams et al.	a: small cohort of IPF patients (N = 14); b: Schistosoma mansoni egg and BLM induced pulmonary fibrosis model.	a: increased BALF expression of IL‐25 and ILC2 in IPF patients; b: IL‐25−/−or IL‐17BR−/− attenuated local expression of IL‐4 and IL‐13 and reduced pulmonary collagen deposition in the two fibrosis model; c: increased numbers of IL‐13+ILC2 following egg challenge; d: ILC2‐depletion dampened pulmonary collagen deposition, reduced IL‐13 and TGFβ1 expression induced by IL‐25 and egg; e: transfer of IL‐13+ILC2 significantly induced collagen deposition.	IL‐25 promotes lung fibrosis in a IL‐13+IL‐17BR+ILC2 dependent fashion.
24	Létuvé et al.	In vitro cell culture of human primary lung fibroblasts.	a: IL‐17BR was constitutively expressed by human primary lung fibroblasts; b: IL‐25 increased expression levels of CCL–5, CCL‐11, GM‐CSF and CXCL‐8; c: TNF‐α potentiated IL‐25's role on induction of GM‐CSF and CXCL‐8.	IL‐25 potentiates the expressions of pro‐inflammatory cytokines by directly acting on lung fibroblasts.
25	Lee et al.	Large cohort of IPF patients (N = 100).	BALF expression level of IL‐25 were not significantly different between Normal control and IPF group	Alveolar IL‐25 was not up‐regulated in IPF.
IL‐33
27	Tajima et al.	Retrospective study with 49 IPF patients.	a: the serum levels of sST2 in AE‐IPF patients were significantly higher than those in IPF patients with stable state and healthy subjects; b: serum ST2 correlated positively with LDH and CRP, and negatively correlated with PaO2 and VC%.	sST2 protein may be the potential biomarker for the inflammatory process in the IPF lung.
28	Tajima et al.	a: BLM‐induced lung fibrosis model; b: in vitro cell culture of human primary lung fibroblasts and AECs.	a: ST2 gene was markedly induced following with the upregulation of Th2‐type cytokines (IL‐4 and IL‐5) and proinflammatory cytokines (IL‐1β and TNF‐α) induced by BLM; b: IL‐1β, TNF‐α and IL‐4 could promote ST2 mRNA expression in both AECs and lung fibroblast.	Elevated sT2 level reflects dysregulated local inflammatory response and the Th2‐type immune milieu in lung fibrosis.
29	Luzina et al.	a: small cohort with 3 patients with IPF; b: BLM‐induced lung fibrosis model.	a: hIL‐33 constitutively expressed in healthy lungs; b: hIL‐33 was much higher in the lungs of IPF patients than control subjects, with inflammatory cells and fibroblasts to be the most intense staining cells; c: flmIL‐33 recruited lymphocytes and neutrophils, and promoted the production of IL‐1β, TNF‐α, IL‐6, MIP‐1a and RANTES; d: ST2L deficiency failed to attenuate flmIL‐33 mediated pulmonary infiltration and the production of the proinflammatory cytokines.	flmIL‐33 mediates non‐atopic lung inflammation in a ST2L‐independent manner
30	Luzina et al.	a: small cohort with 11 patients with IPF; b: BLM‐induced lung fibrosis model.	a: infiltrating cells and stromal cells in IPF lung showed obvious positive staining of IL‐33; b: flmIL‐33 transfection induced significant lung collagen deposition; c: flmIL‐33 transfection further potentiated lung collagen deposition induced by BLM; d: flmIL‐33 plus BLM synergistically aggregated the expression of TGF‐β, MCP‐1, MIP‐1α, IL‐6, TNF‐α, and HSP70	flIL‐33 exhibits a proinflammatory and profibrotic effect in a ST2L and Th2‐independent fashion.
31	Li et al.	BLM‐induced lung fibrosis model.	a: IL‐33 is constitutively expressed in AECs but can be induced in macrophages by BLM; b: ST2 depletion/anti–IL‐33 antibody/alveolar macrophage depletion attenuated bleomycin‐induced IL‐33, IL‐13, TGF‐β1 expression, and disrupted lung collagen deposition. c: Exogenous IL‐33/transfer of ILC2s further potentiated lung inflammation and fibrosis induced by BLM; d: IL‐33 polarized M2 macrophages to produce IL‐13 and TGF‐β1 and induced the expansion of ILC2s to produce IL‐13.	mIL‐33‐ST2L axis potentiates lung inflammation and fibrosis in a M2 macrophages and ILC2s dependent manner.
33	Gao et al.	BLM‐induced lung fibrosis model.	a: sST2 treatment significantly improved survival rate and reduced weight loss induced by BLM challenge; b: sST2 treatment markedly lowered the BALF levels of IL‐4, IL‐6, IL‐13, IL‐33, MCP‐1, TGF‐β1, whereas it increased the levels of IFN‐γ; c: sST2 treatment profoundly attenuated the pulmonary inflammatory cell infiltration and fibrotic changes.	sST2 attenuated lung fibrosis by blocking IL‐33/STL2 axis and down‐regulating proinflammatory and profibrotic mediators.
34	Fanny et al.	BLM‐induced lung fibrosis model.	a: 24 h post‐BLM treatment ST2‐deficient mice displayed augmented inflammatory cell recruitment and edema; b: lung remodeling and fibrosis were decreased with reduced M2 macrophages associated with M2‐like cytokine profile in ST2‐deficient mice.	IL‐33/ST2 promotes lung fibrosis by potentiating M2 macrophages skew.
35	Zhao et al.	a: BLM‐induced lung fibrosis model; b: in vitro cell culture of ILC2/fibroblast	a: ILC2 recruitment, IL‐13 induction, and fibrosis were significantly diminished in ST2‐deficient‐BM chimera mice; b: ILC2 from bleomycin‐treated mice stimulated type I collagen expression in lung fibroblast.	IL‐33/ST2 pathway contributed to fibroblast activation to promote lung fibrosis by recruiting BM‐derived ILC2s.
25	Lee et al.	Large cohort of IPF patients (N = 100).	BALF expression level of IL‐33 were significantly up‐regulated in patients with IPF than normal controls	IL‐33 mediated innate immune responses may be associated with the development of IPF.
TSLP
40	Datta et al.	a: small cohort of IPF patients (N = 12) b: in vitro cell culture of fibroblast	a: TSLP were up‐regulated in AECs, myofibroblasts in IPF lung; b: TSLPR immunostaining was positive on ASMCs, AECs and myofibroblasts in IPF lung; c: TSLP increased CCL2 expression by pHLFs	TSLP promotes lung fibrosis by directly acting on lung fibroblast.
25	Lee et al.	Large cohort of IPF patients (N = 100).	BALF expression level of TSLP were significantly up‐regulated in patients with IPF than normal controls	TSLP mediated innate immune responses may be associated with the development of IPF.

Abbreviations: AECs, alveolar epithelial cells; ASMCs, airway smooth muscle cells; BALF, bronchoalveolar lavage fluid; BLM, bleomycin; BM, bone marrow; CRP, C‐reactive protein; HSP70, heat shock protein 70; IFN‐γ, interferon‐γ; ILC2s, type 2 innate lymphoid cells; IPF, idiopathic pulmonary fibrosis; LDH, lactate dehydrogenase; MCP‐1, monocyte chemoattractant protein‐1; MIP‐1α, macrophage inflammatory protein 1α; pHLFs, PaO₂, arterial partial pressure of oxygen; pulmonary human lung fibroblasts; sST2, soluble ST2; TGF‐β1, transforming growth factor‐β1; TNF‐α, tumor necrosis factor α; TSLP, thymic stromal lymphopoietin; VC%, vital capacity%.