IL-10 induces an immune repressor pathway in sepsis by promoting S100A9 nuclear localization and MDSC development
Authors: Lam Nguyen
Mohamed El Gazzar
Charles E McCall
Ajinkya Kumbhare
Isatou Bah
Journal: Cellular immunology (2018)
Discipline: IMMUNOLOGY
Keywords: Inflammation; Innate immunity; MDSCs; S100A9; Sepsis.
Affiliations: Department of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, TN 37614, United States., Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States., Department of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, TN 37614, United States. Electronic address: .

Abstract:  The myeloid-related protein S100A9 reprograms Gr1+CD11b+ myeloid precursors into myeloid-derived suppressor cells (MDSCs) during murine sepsis. Here, we show that the immunosuppressive cytokine IL-10 supports S100A9 expression and its nuclear localization in MDSCs to function as immune repressors. To support this new concept, we showed that antibody mediated IL-10 blockade in wild-type mice after sepsis induction inhibited MDSC expansion during late sepsis, and that ectopic expression of S100A9 in Gr1+CD11b+ cells from S100A9 knockout mice switched them into the MDSC phenotype only in the presence of IL-10. Knockdown of S100A9 in MDSCs from wild-type mice with late sepsis confirmed our findings in the S100A9 knockout mice. We also found that while both IL-6 and IL-10 can activate S100A9 expression in naive Gr1+CD11b+ cells, only IL-10 can induce S100A9 nuclear localization. These results support that IL-10 drives the molecular path that generates MDSCs and enhances immunosuppression during late sepsis, and inform that targeting this immune repressor path may improve sepsis survival in mice. 

Retracted: No

PubPeer comments:
 Same western blot with slightly different exposure time duplicated in two separate experiments with a horizontal flip. ![file] , 
 Corrigendum November 2020 The authors regret the incorrect publication of Fig. 7C in the original article. The right protein band (S100A9 cytosolic) in the top Western blot image in Fig. 7C was a duplicate of the right band (S100A9 cytosolic) of the top right image in Fig. 7B. This was due to a mistake in the cutting and alignment of the correct bands. The correct bands in Fig. 7C have been restored and are presented below. This correction does not influence the results or any parts of the paper. ![file] The authors would like to apologize for any inconvenience caused. *** Could the authors provide the original scans? , 
 Could the authors also provide the original scans for the blots published in Figures 7B and Figure 7D? Thank you. *** ![file] , 
 I inspected an enlarged image in a power point slide we have. These two bands look very close but they are not the same. Corresponding Author , 
 #4 Dear author, Posting the enlarged images from the Powerpoint slide you found would be very helpful! Can you please do that? In case the image is too big one can use https: imgur.com and post a link. Below an animated comparison made using the low-resolution images in the publised paper. [ click to animate ] ![file] , 
 #4 I agree with the previous comment and would hope that at a minimum, the authors could make the PowerPoint slide available. Reviewing the original scans would be a much better way of dismissing the concerns. As this is a relatively recent paper with NIH funding, one would hope that the original data is still available. #5 Thank you for the helpful illustration. , 
 I cannot see the similarity with my naked eye, but the sensitive tool you use can reveal tiny similarities. You or your associates screened this paper two years ago and alerted me to an error in this same figure, which we corrected then (Fig. 7C), but there was no mention of band similarities in Fig. 7B D. Why are you certain now these two bands are similar? Corresponding Author , 
 #7 Dr. El-Gazzar - Thank you for responding. I appreciate the limitations of visually inspecting published images. Sometimes the publication process obscures differences that are clearly visible in the original images, which is why I requested the original images, or the best available substitute - the PowerPoint slides - if the originals are no longer available. It is a bit surprising that the original scans cannot be found on a recent NIH-funded paper, but either way, it would be helpful if you could provide a link to the PowerPoint slides or post them here. It is clear that these images are very similar, but I cannot be certain that they are the same. As to the original poster (#1), I do not know who that was. I reviewed the paper for the first time as I was scanning [papers with a common co-author] . I would be interested in seeing the original data for the previous correction as well. , 
 Below are the details of a correction made by the authors in June. It is quite confusing to me that a correction would be required when the author in #7, and ORI in an email sent to me on September 15, 2022, both insisted that they determined that these blots were *different* after a forensic analysis. Presumably those assurances to me were in error and the authors have access to the original data from which the data for the correction was extracted. I would like to repeat my request for access to this original data. *** Available online 9 June 2022  The authors regret that the lower S100A9 bands in Fig. 7D are duplicate of the lower S100A9 bands in Fig. 7B and were misplaced during figure assembly. The correct bands in Fig. 7D have been restored. This correction does not influence the results or conclusions of this paper. The authors would like to apologize for any inconvenience caused. ![file] Via https: www.sciencedirect.com science article pii S0008874922000855 , 
 Below a summary and graphical abstract showing the changes to Fig. 7 in time. Just because this is all intriguingly odd. Mesocyclops major (#1) noticed the first duplication-with-mirroring in 2020. 3 months later this got corrected without PubPeer reply. The issue was explained as being due to  a mistake in the cutting and alignment of the correct band (conclusions unaffected). April 2022 Actinopolyspora biskrensis (#3) spotted the second duplication-with-mirroring. This time the author reacted defensive, stating that the data looked different in a **powerpoint slide** (#4). Slide nor original data were ever shared. Even after some prodding the author was not willing to admit to  tiny similarities between the blots (#7). Still, two months later a correction followed:  The authors regret that the lower S100A9 bands in Fig. 7D are duplicate of the lower S100A9 bands in Fig. 7B and were misplaced during figure assembly (conclusions not affected). And for the grand finale: the ORI was signaled for the 2nd duplication and its investigation found... no duplication! With both duplications confirmed in print. And note that none of these could have happened without mirroring and splicing of bands. ![file] ,