TY - JOUR
T1 - Single cell and tissue-transcriptomic analysis of murine bladders reveals age- and TNFα-dependent but microbiota-independent tertiary lymphoid tissue formation
AU - Ligon, Marianne M.
AU - Wang, Caihong
AU - DeJong, Erica N.
AU - Schulz, Christian
AU - Bowdish, Dawn M.E.
AU - Mysorekar, Indira U.
N1 - Funding Information:
We thank Drs. Deborah Frank, Jason Mills, and Paula Saz-Leal for editorial comments, the Genome Technology Access Center (GTAC) for performing and processing sequencing data, and Eric Tycksen for bioinformatic analysis and statistical explanations of tissue RNA-seq data. This work was funded in part by NIH grants R01 AG052494, P20 DK119840, and R56 AG064634 to I.U.M.; T32 GM007200 and T32 AI007172 to M.M.L.; CIHR #153414 to D.M.E.B.; Deutsche Forschungsgemeinschaft fellowship #SCHU3131/1-1 to C.S.; Ontario Early Researchers award to E.N.D.; NIH Shared Instrumentation Grant S10 RR0275523 to Alafi Neuroimmaging Core; and P30 CA91842 and UL1 TR002345 to G.T.A.C.
Publisher Copyright:
© 2020, Society for Mucosal Immunology.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Aging has multifaceted effects on the immune system, but how aging affects tissue-specific immunity is not well-defined. Bladder diseases characterized by chronic inflammation are highly prevalent in older women, but mechanisms by which aging promotes these pathologies remain unknown. Tissue transcriptomics of unperturbed, young and aged bladders identified a highly altered immune landscape as a fundamental feature of the aging female bladder. Detailed mapping of immune cells using single cell RNA-sequencing revealed novel subsets of macrophages and dendritic cells and unique changes to the immune repertoire in the aged bladder. B and T cells are highly enriched in aged bladders and spontaneously form organized bladder tertiary lymphoid tissues (bTLTs). Naïve, activated, and germinal center B cells and IgA+ plasma cells are found within bTLT and associated with increased urinary IgA concentrations. bTLTs form with increasing age and their formation is dependent on TNFα. Microbiota are not required to form bTLT, as aged germfree mice also harbor them. Thus, bTLTs require age-dependent TNFα but are independent of the microbiota. Our results indicate that chronic, age-associated inflammation underlies a fundamental alteration to the bladder and establishes a resource for further investigation of the bladder immune system in homeostasis, aging, and disease.
AB - Aging has multifaceted effects on the immune system, but how aging affects tissue-specific immunity is not well-defined. Bladder diseases characterized by chronic inflammation are highly prevalent in older women, but mechanisms by which aging promotes these pathologies remain unknown. Tissue transcriptomics of unperturbed, young and aged bladders identified a highly altered immune landscape as a fundamental feature of the aging female bladder. Detailed mapping of immune cells using single cell RNA-sequencing revealed novel subsets of macrophages and dendritic cells and unique changes to the immune repertoire in the aged bladder. B and T cells are highly enriched in aged bladders and spontaneously form organized bladder tertiary lymphoid tissues (bTLTs). Naïve, activated, and germinal center B cells and IgA+ plasma cells are found within bTLT and associated with increased urinary IgA concentrations. bTLTs form with increasing age and their formation is dependent on TNFα. Microbiota are not required to form bTLT, as aged germfree mice also harbor them. Thus, bTLTs require age-dependent TNFα but are independent of the microbiota. Our results indicate that chronic, age-associated inflammation underlies a fundamental alteration to the bladder and establishes a resource for further investigation of the bladder immune system in homeostasis, aging, and disease.
UR - http://www.scopus.com/inward/record.url?scp=85085076390&partnerID=8YFLogxK
U2 - 10.1038/s41385-020-0290-x
DO - 10.1038/s41385-020-0290-x
M3 - Article
C2 - 32366865
AN - SCOPUS:85085076390
SN - 1933-0219
VL - 13
SP - 908
EP - 918
JO - Mucosal Immunology
JF - Mucosal Immunology
IS - 6
ER -