TY - JOUR
T1 - Paneth Cell-Derived Lysozyme Defines the Composition of Mucolytic Microbiota and the Inflammatory Tone of the Intestine
AU - Yu, Shiyan
AU - Balasubramanian, Iyshwarya
AU - Laubitz, Daniel
AU - Tong, Kevin
AU - Bandyopadhyay, Sheila
AU - Lin, Xiang
AU - Flores, Juan
AU - Singh, Rajbir
AU - Liu, Yue
AU - Macazana, Carlos
AU - Zhao, Yanlin
AU - Béguet-Crespel, Fabienne
AU - Patil, Karuna
AU - Midura-Kiela, Monica T.
AU - Wang, Daniel
AU - Yap, George S.
AU - Ferraris, Ronaldo P.
AU - Wei, Zhi
AU - Bonder, Edward M.
AU - Häggblom, Max M.
AU - Zhang, Lanjing
AU - Douard, Veronique
AU - Verzi, Michael P.
AU - Cadwell, Ken
AU - Kiela, Pawel R.
AU - Gao, Nan
N1 - Funding Information:
The authors are indebted to Ivaylo I. Ivanov (Columbia University) and Mi-Na Kweon (University of Ulsan College of Medicine) for helpful discussion. We thank Peter Romanienko and Ghassan Yehia (Rutgers Cancer Institute of New Jersey Genome Editing Shared Resource P30CA072720-5922) for deriving Lyz1 −/− and Villin-Lyz1 mice, Luke Fritzk (Digital Imaging and Histology Core) for histology, Sukhwinder Singh and Tammy Mui-Galenkamp (Flow Cytometry and Immunology Core) for FACS analysis, Seema Husain (The Genomics Center) for scRNA sequencing, and the excellent technical support from PrimBio Research Institute (Exton, PA). This work was supported by NIH ( DK102934 , DK119198 , AT010243 , and CA178599 ), NSF/BIO/IDBR ( 1353890 and 1952823 ), ACS Scholar Award ( RSG-15-060-01-TBE ), Rutgers IMRT award (to N.G.); Rutgers Chancellor’s SEED grant (to E.M.B.); NIH ( R01CA190558 to M.P.V., R01AI134040 to G.S.Y., F31 DK121428 to S.B., and 5R01DK109711 to P.R.K.); PANDA Endowment in Autoimmune Diseases (to P.R.K.); NSF ( IOS-1456673 and IOS-1754783 to R.P.F.); NJCCR fellowship ( DCHS19PPC038 to J.F.); and a CCFA Career Development Award ( 406794 to S.Y.).
Funding Information:
The authors are indebted to Ivaylo I. Ivanov (Columbia University) and Mi-Na Kweon (University of Ulsan College of Medicine) for helpful discussion. We thank Peter Romanienko and Ghassan Yehia (Rutgers Cancer Institute of New Jersey Genome Editing Shared Resource P30CA072720-5922) for deriving Lyz1?/? and Villin-Lyz1 mice, Luke Fritzk (Digital Imaging and Histology Core) for histology, Sukhwinder Singh and Tammy Mui-Galenkamp (Flow Cytometry and Immunology Core) for FACS analysis, Seema Husain (The Genomics Center) for scRNA sequencing, and the excellent technical support from PrimBio Research Institute (Exton, PA). This work was supported by NIH (DK102934, DK119198, AT010243, and CA178599), NSF/BIO/IDBR (1353890 and 1952823), ACS Scholar Award (RSG-15-060-01-TBE), Rutgers IMRT award (to N.G.); Rutgers Chancellor's SEED grant (to E.M.B.); NIH (R01CA190558 to M.P.V. R01AI134040 to G.S.Y. F31 DK121428 to S.B. and 5R01DK109711 to P.R.K.); PANDA Endowment in Autoimmune Diseases (to P.R.K.); NSF (IOS-1456673 and IOS-1754783 to R.P.F.); NJCCR fellowship (DCHS19PPC038 to J.F.); and a CCFA Career Development Award (406794 to S.Y.). S.Y. I.B. G.S.Y. K.C. P.R.K. and N.G. formulated the hypothesis, conceptualized the idea, and designed the research. S.Y. I.B. and N.G. wrote the manuscript. S.Y. I.B. D.L. K.T. S.B. J.F. R.S. Y.L. C.M. Y.Z. F.B.-C. K.P. M.T.M.-K. D.W. R.P.F. E.M.B. M.M.H. L.Z. V.D. and M.P.V. performed experiments, analyzed, and reported data. The authors declare no competing interests.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/8/18
Y1 - 2020/8/18
N2 - Paneth cells are the primary source of C-type lysozyme, a β-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn's disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1−/− hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses, with implications for IBD.
AB - Paneth cells are the primary source of C-type lysozyme, a β-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn's disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1−/− hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses, with implications for IBD.
KW - IL-13
KW - Lyz1
KW - Paneth cell
KW - Ruminococcus gnavus
KW - colitis
KW - inflammation
KW - lysozyme
KW - mucolytic bacteria
KW - type 2 immunity
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UR - http://www.scopus.com/inward/citedby.url?scp=85089343497&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2020.07.010
DO - 10.1016/j.immuni.2020.07.010
M3 - Article
C2 - 32814028
AN - SCOPUS:85089343497
SN - 1074-7613
VL - 53
SP - 398-416.e8
JO - Immunity
JF - Immunity
IS - 2
ER -