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Progranulin deficiency promotes neuroinflammation through cathepsin B-mediated activation of the NLRP3 inflammasome
Aggarwal G, Banerjee S, Bhadra AK, Hwang JJ, Malabana DAO, Nagarajan N, Smith DM, Kollarapu J et al.. bioRxiv, 2026-10-13
Topic: Inflammation, microglia and astrocytes
Haploinsufficiency of progranulin (resulting from mutations in the GRN gene) is a major genetic cause of frontotemporal dementia (FTD), which is characterized by profound changes in personality and behavior, progressive impairments in executive function, speech, language and/or movement, TDP-43 pathology, lysosomal dysfunction, and neuroinflammation. Studies in progranulin-deficient mouse models have demonstrated the critical role of neuroinflammation in disease pathogenesis, as deletion of NF-kB or complement factors prevents FTD-associated behavioral deficits. While progranulin is known to be anti-inflammatory, the precise molecular mechanism by which its deficiency triggers inflammatory cascades remain unclear. Here, we investigate the involvement of the NLRP3 inflammasome in progranulin-deficient models, including mice, human microglial cells, and patient fibroblasts. In Grn mice, we found increased levels of several inflammasome-related proteins, including procaspase-1 and cleaved IL-1β. Similarly, GRN knockout (KO) microglia cells showed significant increases in levels of procaspase-1, NLRP3, and cleaved IL-1β. Moreover, KO cells had increased NLRP3 oligomerization, suggesting that progranulin negatively regulates inflammasome assembly. We also investigated the potential link between lysosomal dysfunction and NLRP3 inflammasome activation in progranulin deficiency. We found that pharmacological inhibition of cathepsin B reduced NLRP3 inflammasome oligomerization as well as inflammatory cytokine expression in GRN KO cells. Additionally, siRNA knockdown of cathepsin B reduced levels of procaspase-1 and cleaved IL-1β in GRN KO cells. Finally, we found that heterozygous GRN fibroblasts exhibited similar increases in procaspase-1 and cleaved IL-1β levels, and these increases were corrected by treatment with an antisense oligonucleotide (ASO) that increase progranulin protein levels. Overall, our results demonstrate that progranulin deficiency promotes NLRP3 inflammasome assembly and activity through cathepsin B-mediated signaling, thereby establishing a mechanistic link between lysosomal dysfunction and increased inflammation. The ability of the GRN -targeting ASO to correct NLRP3-mediated inflammation highlights a promising therapeutic strategy for FTD- GRN and inflammation in other neurodegenerative disorders linked to progranulin deficiency.
Key findings
- Studies in progranulin-deficient mouse models have demonstrated the critical role of neuroinflammation in disease pathogenesis, as deletion of NF-kB or complement factors prevents FTD-associated behavioral deficits.
- In Grn mice, we found increased levels of several inflammasome-related proteins, including procaspase-1 and cleaved IL-1β.
- Similarly, GRN knockout (KO) microglia cells showed significant increases in levels of procaspase-1, NLRP3, and cleaved IL-1β.
- Moreover, KO cells had increased NLRP3 oligomerization, suggesting that progranulin negatively regulates inflammasome assembly.
- We found that pharmacological inhibition of cathepsin B reduced NLRP3 inflammasome oligomerization as well as inflammatory cytokine expression in GRN KO cells.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Aggarwal, G., Banerjee, S., Bhadra, A. K., Hwang, J. J., Malabana, D. A. O., Nagarajan, N., et al. (2026). Progranulin deficiency promotes neuroinflammation through cathepsin B-mediated activation of the NLRP3 inflammasome. bioRxiv. https://doi.org/10.64898/2026.10.11.758389
Vancouver
Aggarwal G, Banerjee S, Bhadra AK, Hwang JJ, Malabana DAO, Nagarajan N, et al. Progranulin deficiency promotes neuroinflammation through cathepsin B-mediated activation of the NLRP3 inflammasome. bioRxiv. 2026. doi:10.64898/2026.10.11.758389.
BibTeX
@article{aggarwal2026-715fc47c,
author = {Aggarwal, G. and Banerjee, S. and Bhadra, A. K. and Hwang, J. J. and Malabana, D. A. O. and Nagarajan, N. and Smith, D. M. and Kollarapu, J. and others},
title = {{Progranulin deficiency promotes neuroinflammation through cathepsin B-mediated activation of the NLRP3 inflammasome}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.11.758389},
url = {https://doi.org/10.64898/2026.10.11.758389}
}
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