Enteric Ner­vous Sys­tem-Derived VIP Restrains Dif­fer­en­ti­a­tion of LGR5+ Stem Cells Towards the Secre­to­ry Lin­eage Imped­ing Type 2 Immune Programs

Intesti­nal epithe­lial home­osta­sis is sus­tained by the con­tin­u­ous dif­fer­en­ti­a­tion of stem cells that are locat­ed at the bot­tom of thein­testi­nal crypts. Epithe­lial renew­al is a high­ly dynam­ic process that receives sig­nal­ing input from var­i­ous cel­lu­lar sys­tems to secure bar­ri­er func­tion and nutri­ent uptake.

Here, we addressed the role of the enteric ner­vous sys­tem (ENS) in this process. We iden­ti­fy a piv­otal func­tion of the ENS in con­trol­ling epithe­lial pro­lif­er­a­tion, dif­fer­en­ti­a­tion, and mucos­al home­osta­sis. Neu­ronal Vasoac­tive Intesti­nal Pep­tide (VIP), act­ing via its recep­tor VIPR1 expressed by epithe­lial stem cells, restrains pro­lif­er­a­tion and dif­fer­en­ti­a­tion towards the secre­to­ry lin­eage. Defi­cien­cy of VIP or VIPR1 led to an increase in secre­to­ry epithe­lial cells, includ­ing tuft cells, increased IL-25 expres­sion, and acti­va­tion of ILC2.

Func­tion­al­ly, VIP defi­cien­cy improved worm expul­sion and exac­er­bat­ed aller­gic lung inflam­ma­tion. Our data expose a pre­vi­ous­ly unap­pre­ci­at­ed role for the ENS in dic­tat­ing epithe­lial cell fate deci­sions, there­by estab­lish­ing a neu­ro-epithe­lial unit as a crit­i­cal check­point for ILC2 and type 2 immu­ni­ty, com­ple­ment­ing the well-known reg­u­la­tors of bar­ri­er integri­ty and mucos­al home­osta­sis, name­ly the com­men­sal micro­bio­ta, the epithe­lial bar­ri­er, and the immune system.

Intesti­nal epithe­lial home­osta­sis is sus­tained by the con­tin­u­ous dif­fer­en­ti­a­tion of stem cells that are locat­ed at the bot­tom of thein­testi­nal crypts. Epithe­lial renew­al is a high­ly dynam­ic process that receives sig­nal­ing input from var­i­ous cel­lu­lar sys­tems to secure bar­ri­er func­tion and nutri­ent uptake.

Here, we addressed the role of the enteric ner­vous sys­tem (ENS) in this process. We iden­ti­fy a piv­otal func­tion of the ENS in con­trol­ling epithe­lial pro­lif­er­a­tion, dif­fer­en­ti­a­tion, and mucos­al home­osta­sis. Neu­ronal Vasoac­tive Intesti­nal Pep­tide (VIP), act­ing via its recep­tor VIPR1 expressed by epithe­lial stem cells, restrains pro­lif­er­a­tion and dif­fer­en­ti­a­tion towards the secre­to­ry lin­eage. Defi­cien­cy of VIP or VIPR1 led to an increase in secre­to­ry epithe­lial cells, includ­ing tuft cells, increased IL-25 expres­sion, and acti­va­tion of ILC2.

Func­tion­al­ly, VIP defi­cien­cy improved worm expul­sion and exac­er­bat­ed aller­gic lung inflam­ma­tion. Our data expose a pre­vi­ous­ly unap­pre­ci­at­ed role for the ENS in dic­tat­ing epithe­lial cell fate deci­sions, there­by estab­lish­ing a neu­ro-epithe­lial unit as a crit­i­cal check­point for ILC2 and type 2 immu­ni­ty, com­ple­ment­ing the well-known reg­u­la­tors of bar­ri­er integri­ty and mucos­al home­osta­sis, name­ly the com­men­sal micro­bio­ta, the epithe­lial bar­ri­er, and the immune system.

Enteric Nervous System-Derived VIP Restrains Differentiation of LGR5+ Stem Cells Towards the Secretory Lineage Impeding Type 2 Immune Programs
Enteric Nervous System-Derived VIP Restrains Differentiation of LGR5+ Stem Cells Towards the Secretory Lineage Impeding Type 2 Immune Programs
Enteric Nervous System-Derived VIP Restrains Differentiation of LGR5+ Stem Cells Towards the Secretory Lineage Impeding Type 2 Immune Programs

Christoph Klose

Christoph Klose earned his Ph.D. in Mol­e­c­u­lar Med­i­cine from Albert-Lud­wigs-Uni­ver­si­ty in Freiburg in 2007. Fol­low­ing his doc­tor­al stud­ies, he con­duct­ed post-doc­tor­al research at Weill Cor­nell Med­i­cine in New York City before estab­lish­ing an inde­pen­dent Emmy-Noe­ther research group at the Depart­ment of Micro­bi­ol­o­gy, Infec­tious Dis­eases, and Immunol­o­gy of Char­ité — Uni­ver­sitätsmedi­zin Berlin. 

Dr. Klose’s research has sig­nif­i­cant­ly con­tributed to our under­stand­ing of immune cell lin­eage com­mit­ment and devel­op­ment, with a par­tic­u­lar focus on innate lym­phoid cells (ILCs). 

In recog­ni­tion of his con­tri­bu­tions, he was award­ed the Robert Koch post-doc­tor­al Immunol­o­gy award in 2015 and has been list­ed as a High­ly Cit­ed Researcher by Clar­i­vate Ana­lyt­ics since 2020. The main focus areas of his research group are (1) The inter­ac­tion between the immune sys­tem and the ner­vous sys­tem, par­tic­u­lar­ly at bar­ri­er sur­faces, and (2) the role of ILC2s in type 2 immunity.

More about Dr. Christoph Klose.

Christoph Klose earned his Ph.D. in Mol­e­c­u­lar Med­i­cine from Albert-Lud­wigs-Uni­ver­si­ty in Freiburg in 2007. Fol­low­ing his doc­tor­al stud­ies, he con­duct­ed post-doc­tor­al research at Weill Cor­nell Med­i­cine in New York City before estab­lish­ing an inde­pen­dent Emmy-Noe­ther research group at the Depart­ment of Micro­bi­ol­o­gy, Infec­tious Dis­eases, and Immunol­o­gy of Char­ité — Uni­ver­sitätsmedi­zin Berlin. 

Dr. Klose’s research has sig­nif­i­cant­ly con­tributed to our under­stand­ing of immune cell lin­eage com­mit­ment and devel­op­ment, with a par­tic­u­lar focus on innate lym­phoid cells (ILCs). 

In recog­ni­tion of his con­tri­bu­tions, he was award­ed the Robert Koch post-doc­tor­al Immunol­o­gy award in 2015 and has been list­ed as a High­ly Cit­ed Researcher by Clar­i­vate Ana­lyt­ics since 2020. The main focus areas of his research group are (1) The inter­ac­tion between the immune sys­tem and the ner­vous sys­tem, par­tic­u­lar­ly at bar­ri­er sur­faces, and (2) the role of ILC2s in type 2 immunity.

Christoph Klose | Enteric Nervous System-Derived VIP Restrains Differentiation of LGR5+ Stem Cells Towards the Secretory Lineage Impeding Type 2 Immune Programs
Christoph Klose, Char­ité – Berlin Uni­ver­si­ty Med­i­cine, GERMANY

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