TY  - JOUR
AB  - The immune balance in mucosal tissues depends on a delicate interplay between inflammatory T helper 17 (Th17) cells and immunosuppressive regulatory T cells (Tregs). But what happens when this balance is disturbed? In this study, we uncovered a critical role for acyl-CoA synthetase bubblegum family member 1 (Acsbg1) in shaping Th17and Treg dynamics. Using Acsbg1-deficient mice, we show that while its absence does not disrupt homeostasis under steady-state conditions, it significantly alters Treg populations, particularly in gut-associated tissues. Under high-fat diet-induced metabolic stress, Acsbg1-deficient mice display mild metabolic changes but maintain systemic immune and metabolic function, indicating that Acsbg1 is dispensable for metabolic adaptation in vivo. However, upon infection with Citrobacter rodentium, these mice exhibit excessive Th1/Th17-driven inflammation and impaired resolution, accompanied by a strong reduction in IL-10-producing and ST2+ Treg subsets. The impact is even more striking in an adoptive transfer colitis model, where Acsbg1-deficient Tregs fail to control inflammation, resulting in severe colitis and tissue damage. Our findings identify Acsbg1 as a key regulator of ST2+ Treg function and a central player in mucosal immune homeostasis, highlighting its potential as a therapeutic target for inflammatory bowel disease and colorectal cancer.
AU  - Palatella, M.*
AU  - Kruse, F.*
AU  - Ji, H.
AU  - Loriani Fard, A.K.*
AU  - Becker, M.
AU  - Daniel, C.
AU  - Rohm, M.
AU  - Huehn, J.*
C1  - 75916
C2  - 58185
TI  - Acsbg1 maintains intestinal immune homeostasis and controls inflammation by regulating ST2+ Tregs.
JO  - Mucosal Immunol.
PY  - 2025
SN  - 1933-0219
ER  - 

TY  - JOUR
AB  - Peripherally induced regulatory T cells (pTregs) expressing the retinoic acid receptor-related orphan-receptor gamma t (RORγt) are indispensable for intestinal immune homeostasis. NF-κB family members regulate the differentiation of thymic Tregs and promote their survival in the periphery. However, the Treg-intrinsic molecular mechanisms controling the size of the pTregs in the intestine and associated lymphoid organs remain unclear. Here, we provide direct evidence that Bcl3 limits the development of pTregs in a T cell-intrinsic manner. Moreover, the absence of Bcl3 allowed for the formation of an unusual intestinal Treg population co-expressing the transcription factors Helios and RORγt. The expanded RORγt+ Treg populations in the absence of Bcl3 displayed an activated phenotype and secreted high levels of the anti-inflammatory cytokines IL-10 and TGFβ. They were fully capable of suppressing effector T cells in a transfer colitis model despite an intrinsic bias to trans-differentiate toward Th17-like cells. Finally, we provide a Bcl3-dependent gene signature in pTregs including altered responsiveness to the cytokines IL-2, IL-6, and TNFα. Our results demonstrate that Bcl3 acts as a molecular switch to limit the expansion of different intestinal Treg subsets and may thus serve as a novel therapeutic target for inflammatory bowel disease by restoring intestinal immune tolerance.
AU  - Köhler, A.
AU  - Geiselhöringer, A.-L.
AU  - Kolland, D.
AU  - Kreft, L.
AU  - Wichmann, N.
AU  - Hils, M.*
AU  - Szente-Pasztoi, M.
AU  - Zurkowski, E.*
AU  - Vogt, J.*
AU  - Kübelbeck, T.*
AU  - Biedermann, T.*
AU  - Schmitz, I.*
AU  - Hansen, W.*
AU  - Kramer, D.*
AU  - Gaida, M.M.*
AU  - Schmidt-Weber, C.B.
AU  - Hoevelmeyer, N.*
AU  - Ohnmacht, C.
C1  - 70560
C2  - 55687
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 673-691
TI  - The atypical IκB family member Bcl3 determines differentiation and fate of intestinal RORγt+ regulatory T cell subsets.
JO  - Mucosal Immunol.
VL  - 17
IS  - 4
PB  - Elsevier Science Inc
PY  - 2024
SN  - 1933-0219
ER  - 

TY  - JOUR
AB  - Monocyte-derived macrophages (MDM) drive the inflammatory response to 
      severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and they 
      are a major source of eicosanoids in airway inflammation. Here we report
       that MDM from SARS-CoV-2-infected individuals with mild disease show an
       inflammatory transcriptional and metabolic imprint that lasts for at 
      least 5 months after SARS-CoV-2 infection. MDM from convalescent 
      SARS-CoV-2-infected individuals showed a downregulation of pro-resolving
       factors and an increased production of pro-inflammatory eicosanoids, 
      particularly 5-lipoxygenase-derived leukotrienes. Leukotriene synthesis 
      was further enhanced by glucocorticoids and remained elevated at 3–5 
      months, but had returned to baseline at 12 months post SARS-CoV-2 
      infection. Stimulation with SARS-CoV-2 spike protein or LPS triggered 
      exaggerated prostanoid-, type I IFN-, and chemokine responses in post 
      COVID-19 MDM. Thus, SARS-CoV-2 infection leaves an inflammatory imprint 
      in the monocyte/ macrophage compartment that drives aberrant macrophage 
      effector functions and eicosanoid metabolism, resulting in long-term 
      immune aberrations in patients recovering from mild COVID-19.
AU  - Bohnacker, S.
AU  - Hartung, F.
AU  - Henkel, F.
AU  - Quaranta, A.*
AU  - Kolmert, J.*
AU  - Priller, A.*
AU  - Ud-Dean, M.
AU  - Giglberger, J.*
AU  - Kugler, L.M.*
AU  - Pechtold, L.*
AU  - Yazici, S.*
AU  - Lechner, A.
AU  - Erber, J.*
AU  - Protzer, U.
AU  - Lingor, P.*
AU  - Knolle, P.*
AU  - Chaker, A.
AU  - Schmidt-Weber, C.B.
AU  - Wheelock, C.E.*
AU  - Esser-von Bieren, J.
C1  - 64606
C2  - 52341
SP  - 515–524
TI  - Mild COVID-19 imprints a long-term inflammatory eicosanoid- and chemokine memory in monocyte-derived macrophages.
JO  - Mucosal Immunol.
VL  - 15
PY  - 2022
SN  - 1933-0219
ER  - 

TY  - JOUR
AB  - The original version of this article contained an error in the ESM. The supplemental file titled “Supplementary information 1” is a marked version of the correct file, “Supplementary information 2”. “Supplementary information 1” was therefore removed. The authors apologize for the error. The original article has been corrected.
AU  - Bohnacker, S.
AU  - Hartung, F.
AU  - Henkel, F.
AU  - Quaranta, A.*
AU  - Kolmert, J.*
AU  - Priller, A.*
AU  - Ud-Dean, M.
AU  - Giglberger, J.*
AU  - Kugler, L.M.*
AU  - Pechtold, L.*
AU  - Yazici, S.*
AU  - Lechner, A.
AU  - Erber, J.*
AU  - Protzer, U.
AU  - Lingor, P.*
AU  - Knolle, P.*
AU  - Chaker, A.
AU  - Schmidt-Weber, C.B.
AU  - Wheelock, C.E.*
AU  - Esser-von Bieren, J.
C1  - 64995
C2  - 52607
TI  - Correction to: Mild COVID-19 imprints a long-term inflammatory eicosanoid- and chemokine memory in monocyte-derived macrophages.
JO  - Mucosal Immunol.
VL  - 15
PY  - 2022
SN  - 1933-0219
ER  - 

TY  - JOUR
AB  - Immunological memory of innate immune cells, also termed "trained immunity", allows for cross-protection against distinct pathogens, but may also drive chronic inflammation. Recent studies have shown that memory responses associated with type 2 immunity do not solely rely on adaptive immune cells, such as T- and B cells, but also involve the innate immune system and epithelial cells. Memory responses have been described for monocytes, macrophages and airway epithelial cells of asthmatic patients as well as for macrophages and group 2 innate lymphoid cells (ILC2) from allergen-sensitized or helminth-infected mice. The metabolic and epigenetic mechanisms that mediate allergen- or helminth-induced reprogramming of innate immune cells are only beginning to be uncovered. Trained immunity has been implicated in helminth-driven immune regulation and allergen-specific immunotherapy, suggesting its exploitation in future therapies. Here, we discuss recent advances and key remaining questions regarding the mechanisms and functions of trained type 2 immunity in infection and inflammation.
AU  - Hartung, F.
AU  - Esser-von Bieren, J.
C1  - 66175
C2  - 52759
SP  - 1158-1169
TI  - Trained immunity in type 2 immune responses.
JO  - Mucosal Immunol.
VL  - 15
IS  - 6
PY  - 2022
SN  - 1933-0219
ER  - 

TY  - JOUR
AB  - The original version of this article unfortunately contained a mistake in the figure legends as the following statement was missing “Created with BioRender.com”. The original article has been corrected.
AU  - Hartung, F.
AU  - Esser-von Bieren, J.
C1  - 66261
C2  - 52758
TI  - Correction to: Trained immunity in type 2 immune responses (Mucosal Immunology, (2022), 10.1038/s41385-022-00557-0).
JO  - Mucosal Immunol.
PY  - 2022
SN  - 1933-0219
ER  - 

TY  - JOUR
AB  - Molecular mechanisms that regulate lung repair vs. progressive scarring in pulmonary fibrosis remain elusive. Interleukin (IL)-4 and IL-13 are pro-fibrotic cytokines that share common receptor chains including IL-13 receptor (R) α1 and are key pharmacological targets in fibrotic diseases. However, the roles of IL-13Rα1 in mediating lung injury/repair are unclear. We report dysregulated levels of IL-13 receptors in the lungs of bleomycin-treated mice and to some extent in idiopathic pulmonary fibrosis patients. Transcriptional profiling demonstrated an epithelial cell-associated gene signature that was homeostatically dependent on IL-13Rα1 expression. IL-13Rα1 regulated a striking array of genes in the lung following bleomycin administration and Il13ra1 deficiency resulted in exacerbated bleomycin-induced disease. Increased pathology in bleomycin-treated Il13ra1(-/-) mice was due to IL-13Rα1 expression in structural and hematopoietic cells but not due to increased responsiveness to IL-17, IL-4, IL-13, increased IL-13Rα2 or type 1 IL-4R signaling. These data highlight underappreciated protective roles for IL-13Rα1 in lung injury and homeostasis.
AU  - Karo-Atar, D.*
AU  - Bordowitz, A.*
AU  - Wand, O.*
AU  - Pasmanik-Chor, M.*
AU  - Fernandez, I.E.
AU  - Itan, M.*
AU  - Frenkel, R.*
AU  - Herbert, D.R.*
AU  - Finkelman, F.D.*
AU  - Eickelberg, O.
AU  - Munitz, A.*
C1  - 46306
C2  - 37486
SP  - 240-253
TI  - A protective role for IL-13 receptor α 1 in bleomycin-induced pulmonary injury and repair.
JO  - Mucosal Immunol.
VL  - 9
IS  - 1
PY  - 2016
SN  - 1933-0219
ER  - 

TY  - JOUR
AB  - Interferon-γ (IFN-γ) and interleukin-4 (IL-4) are key effector cytokines for the differentiation of T helper type 1 and 2 (Th1 and Th2) cells. Both cytokines induce fate-decisive transcription factors such as GATA3 and TBX21 that antagonize the polarized development of opposite phenotypes by direct regulation of each other's expression along with many other target genes. Although it is well established that mesenchymal cells directly respond to Th1 and Th2 cytokines, the nature of antagonistic differentiation programs in airway epithelial cells is only partially understood. In this study, primary normal human bronchial epithelial cells (NHBEs) were exposed to IL-4, IFN-γ, or both and genome-wide transcriptome analysis was performed. The study uncovers an antagonistic regulation pattern of IL-4 and IFN-γ in NHBEs, translating the Th1/Th2 antagonism directly in epithelial gene regulation. IL-4- and IFN-γ-induced transcription factor hubs form clusters, present in antagonistically and polarized gene regulation networks. Furthermore, the IL-4-dependent induction of IL-24 observed in rhinitis patients was downregulated by IFN-γ, and therefore IL-24 represents a potential biomarker of allergic inflammation and a Th2 polarized condition of the epithelium.
AU  - Zissler, U.M.
AU  - Chaker, A.
AU  - Effner, R.
AU  - Ulrich, M.
AU  - Guerth, F.
AU  - Piontek, G.*
AU  - Dietz, K.
AU  - Regn, M.*
AU  - Knapp, B.
AU  - Theis, F.J.
AU  - Heine, H.*
AU  - Suttner, K.
AU  - Schmidt-Weber, C.B.
C1  - 47340
C2  - 39274
CY  - New York
SP  - 917-926
TI  - Interleukin-4 and interferon-γ orchestrate an epithelial polarization in the airways.
JO  - Mucosal Immunol.
VL  - 9
IS  - 4
PB  - Nature Publishing Group
PY  - 2016
SN  - 1933-0219
ER  - 

TY  - JOUR
AB  - Loss of intestinal epithelial cell (IEC) homeostasis and apoptosis negatively affect intestinal barrier function. Uncontrolled activation of the unfolded protein response (UPR) in IEC contributes to an impaired barrier and is implicated in the pathogenesis of inflammatory bowel diseases. However, the contribution of the UPR target gene C/EBP homologous protein (CHOP), an apoptosis-associated transcription factor, to inflammation-related disease susceptibility remains unclear. Consistent with observations in patients with ulcerative colitis, we show that despite UPR activation in the epithelium, CHOP expression was reduced in mouse models of T-cell-mediated and bacteria-driven colitis. To elucidate the molecular mechanisms of IEC-specific CHOP expression, we generated a conditional transgenic mouse model (Chop(IEC Tg/Tg)). Chop overexpression increased the susceptibility toward dextran sodium sulfate (DSS)-induced intestinal inflammation and mucosal tissue injury. Furthermore, a delayed recovery from DSS-induced colitis and impaired closure of mechanically induced mucosal wounds was observed. Interestingly, these findings seemed to be independent of CHOP-mediated apoptosis. In vitro and in vivo cell cycle analyses rather indicated a role for CHOP in epithelial cell proliferation. In conclusion, these data show that IEC-specific overexpression impairs epithelial cell proliferation and mucosal tissue regeneration, suggesting an important role for CHOP beyond mediating apoptosis.
AU  - Waldschmitt, N.*
AU  - Berger, E.*
AU  - Rath, E.*
AU  - Sartor, R.B.*
AU  - Weigmann, B.*
AU  - Heikenwälder, M.
AU  - Gerhard, M.*
AU  - Janssen, K.P.*
AU  - Haller, D.*
C1  - 31361
C2  - 34487
CY  - New York
SP  - 1452-1466
TI  - C/EBP homologous protein inhibits tissue repair in response to gut injury and is inversely regulated with chronic inflammation.
JO  - Mucosal Immunol.
VL  - 7
IS  - 6
PB  - Nature Publishing Group
PY  - 2014
SN  - 1933-0219
ER  -